Brush-poly (glycoamidoamine)-lipids and uses thereof

Abstract

The present disclosure provides brush-poly(glycoamidoamine)-lipids (PGALs) (e.g., polymers of any one of Formulae (I)-(IV)) and methods of preparing the PGALs. A described PGAL may include poly(glycoamidoamine)-derived moieties (e.g., ##STR00001##
such as ##STR00002##
which may assist the PGAL and/or a complex of the PGAL and an agent to pass through cell membranes or be taken up by cells. Also provided are compositions including a described PGAL and an agent (e.g., polynucleotide, small molecule, peptide, or protein). The present disclosure also provides methods, kits, and uses that include or involve the PGALs or compositions for delivering an agent to a subject, tissue, or cell and/or for treating and/or preventing in a subject a range of diseases, such as genetic diseases, proliferative diseases, hematological diseases, neurological diseases, immunological diseases, gastrointestinal diseases, respiratory diseases, painful conditions, psychiatric disorders, musculoskeletal diseases, genitourinary diseases, and metabolic disorders ##STR00003##

Claims

1. A polymer of the formula: ##STR00447## or a salt thereof, wherein: each instance of X.sup.A is independently substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted carbocyclyl, unsubstituted carbocyclyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, OR.sup.XA, N(R.sup.XA).sub.2, SR.sup.XA, C(NR.sup.XA)R.sup.XA, C(NR.sup.XA)OR.sup.XA, C(NR.sup.XA)N(R.sup.XA).sub.2, C(O)R.sup.XA, C(O)OR.sup.XA, or C(O)N(R.sup.XA).sub.2, wherein each instance of R.sup.XA is independently hydrogen, substituted acyl, unsubstituted acyl, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted carbocyclyl, unsubstituted carbocyclyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XA are joined to form a substituted heterocyclic ring, unsubstituted heterocyclic ring, substituted heteroaryl ring, or unsubstituted heteroaryl ring; each instance of Y.sup.A is independently O, S, or NR.sup.YA, wherein each instance of R.sup.YA is independently hydrogen, substituted C.sub.1-6 alkyl, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each instance of R.sup.A is independently hydrogen, a moiety of the formula: ##STR00448## or a moiety of the formula: ##STR00449## provided that at least about 60% of the total instances of R.sup.A are of the formula: ##STR00450## wherein: each instance of R.sup.A1 is independently hydrogen, substituted alkyl, unsubstituted alkyl, substituted alkenyl, or unsubstituted alkenyl; each instance of R.sup.A2 is independently hydrogen substituted alkyl, or unsubstituted alkyl; and each instance of R.sup.A3 is independently hydrogen substituted alkyl, or unsubstituted alkyl; each instance of a is 1, 2, 3, 4, or 5; each instance of k is 1, 2, 3, 4, 5, or 6; each instance of u is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer between 1 and 1000, inclusive.

2. The polymer of claim 1, wherein the polymer is of the formula: ##STR00451## or a salt thereof.

3. The polymer of claim 1, wherein the polymer is of the formula: ##STR00452## or a salt thereof.

4. The polymer of claim 1, wherein the polymer is of the formula: ##STR00453## or a salt thereof.

5. The polymer of claim 1, or a salt thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula: ##STR00454## or a moiety of the formula: ##STR00455## provided that at least one instance of R.sup.A is of the formula: ##STR00456## wherein each instance of R.sup.A1 is independently unsubstituted C.sub.4-18 alkyl.

6. The polymer of claim 1, or a salt thereof, wherein at least one instance of X.sup.A is OR.sup.XA or N(R.sup.XA).sub.2.

7. The polymer of claim 1, or a salt thereof, wherein at least about 60% of the total instances of R.sup.A are independently of the formula: ##STR00457##

8. The polymer of claim 1, or a salt thereof, wherein each instance of R.sup.A1 is independently substituted C.sub.1-30 alkyl, unsubstituted C.sub.1-30 alkyl, substituted C.sub.2-30 alkenyl, or unsubstituted C.sub.2-30 alkenyl.

9. The polymer of claim 1, or a salt thereof, wherein each instance of R.sup.A2 is hydrogen.

10. The polymer of claim 1, or a salt thereof, wherein each instance of R.sup.A3 is hydrogen.

11. The polymer of claim 1, or a salt thereof, wherein each instance of a is 1 or 2.

12. The polymer of claim 1, or a salt thereof, wherein each instance of k is 1, 2, 3, or 4.

13. The polymer of claim 1, or a salt thereof, wherein each instance of u is 2, 3, or 4.

14. The polymer of claim 1, or a salt thereof, wherein p is an integer between 1 and 30, inclusive.

15. A polymer of the formula: ##STR00458## or a salt thereof, wherein: each instance of X.sup.B is independently substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted carbocyclyl, unsubstituted carbocyclyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, OR.sup.XB, N(R.sup.XB).sub.2, SR.sup.XB, CN, SCN, C(NR.sup.XB)R.sup.XB, C(NR.sup.XB)OR.sup.XB, C(NR.sup.XB)N(R.sup.XB).sub.2, C(O)R.sup.XB, C(O)OR.sup.XB, or C(O)N(R.sup.XB).sub.2, NO.sub.2, NR.sup.XBC(O)R.sup.XB, NR.sup.XBC(O)OR.sup.XB, NR.sup.XBC(O)N(R.sup.XB).sub.2, OC(O)R.sup.XB, OC(O)OR.sup.XB, or OC(O)N(R.sup.XB).sub.2, wherein each instance of R.sup.XB is independently hydrogen, substituted acyl, unsubstituted acyl, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted carbocyclyl, unsubstituted carbocyclyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XB are joined to form a substituted heterocyclic ring, unsubstituted heterocyclic ring, substituted heteroaryl ring, or unsubstituted heteroaryl ring; each instance of Y.sup.B is independently O, S, or NR.sup.YB, wherein each instance of R.sup.YB is independently hydrogen, substituted C.sub.1-6 alkyl, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each instance of R.sup.B is independently hydrogen or a moiety of the formula: ##STR00459## provided that at least about 60% of the total instances of R.sup.B are of the formula: ##STR00460## wherein each instance of R.sup.B1 is independently substituted alkyl, unsubstituted alkyl, substituted alkenyl, or unsubstituted alkenyl; each instance of b is 1, 2, 3, 4, or 5; each instance of m is 1, 2, 3, 4, 5, or 6; each instance of v is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and q is an integer between 1 and 1000, inclusive.

16. A polymer of the formula: ##STR00461## or a salt thereof, wherein: each instance of X.sup.C is independently substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted carbocyclyl, unsubstituted carbocyclyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, OR.sup.XC, N(R.sup.XC).sub.2, SR.sup.XC, CN, SCN, C(NR.sup.XC)R.sup.XC, C(NR.sup.XC)OR.sup.XC, C(NR.sup.XC)N(R.sup.XC).sub.2, C(O)R.sup.XC, C(O)OR.sup.XC, or C(O)N(R.sup.XC).sub.2, NO.sub.2, NR.sup.XCC(O)R.sup.XC, NR.sup.XCC(O)OR.sup.XC, NR.sup.XCC(O)N(R.sup.XC).sub.2, OC(O)R.sup.XC, OC(O)OR.sup.XC, or OC(O)N(R.sup.XC).sub.2, wherein each instance of R.sup.XC is independently hydrogen, substituted acyl, unsubstituted acyl, substituted alkyl, unsubstituted alkyl, substituted alkenyl, unsubstituted alkenyl, substituted alkynyl, unsubstituted alkynyl, substituted carbocyclyl, unsubstituted carbocyclyl, substituted heterocyclyl, unsubstituted heterocyclyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XC are joined to form a substituted heterocyclic ring, unsubstituted heterocyclic ring, substituted heteroaryl ring, or unsubstituted heteroaryl ring; each instance of Y.sup.C is independently O, S, or NR.sup.YC, wherein each instance of R.sup.YC is independently hydrogen, substituted C.sub.1-6 alkyl, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each instance of R.sup.C is independently hydrogen or a moiety of the formula: ##STR00462## provided that at least one instance of R.sup.C is of the formula: ##STR00463## wherein: each instance of Z is independently Oor NR.sup.C4; each instance of R.sup.C1 is independently hydrogen, substituted alkyl, unsubstituted alkyl, substituted alkenyl, or unsubstituted alkenyl; each instance of R.sup.C2 is independently hydrogen substituted alkyl, or unsubstituted alkyl; each instance of R.sup.C3 is independently hydrogen substituted alkyl, or unsubstituted alkyl; and each instance of R.sup.C4 is independently hydrogen, substituted C.sub.1-6 alkyl, unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each instance of c is 1, 2, 3, 4, or 5; each instance of n is 0, 1, 2, 3, 4, 5, or 6; each instance of w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and r is an integer between 1 and 1000, inclusive.

17. A particle comprising a polymer of claim 1, or a salt thereof, and an agent.

18. A composition comprising: a polymer of claim 1, or a salt thereof; an agent; and optionally an excipient.

19. A method of delivering an agent to a subject or cell, the method comprising administering to the subject or contacting the cell with a composition of claim 18.

20. The polymer of claim 1, or a salt thereof, wherein each instance of R.sup.A1 is independently unsubstituted C.sub.4-18 alkyl.

21. The polymer of claim 1, wherein the polymer is prepared by reacting a poly(glycoamidoamine) and an epoxide as shown in the table below: TABLE-US-00014 Poly(glycoamidoamine) Epoxide Polymer Number Number Number TarN1C8 A1a A2b TarN1C10 A1a A2c TarN1C12 A1a A2d TarN1C14 A1a A2e TarN2C8 A1b A2b TarN2C10 A1b A2c TarN2C12 A1b A2d TarN2C14 A1b A2e TarN3C8 A1c A2b A1c A2c TarN3C12 A1c A2d TarN3C14 A1c A2e TarN4C8 A1d A2b TarN4C10 A1d A2c TarN4C12 A1d A2d TarN4C14 A1d A2e GalN2C8 A1e A2b GalN2C10 A1e A2c GalN2C12 A1e A2d GalN2C14 A1e A2e GalN3C8 A1f A2b GalN3C10 A1f A2c GalN3C12 A1f A2d GalN3C14 A1f A2e GalN4C8 A1g A2b GalN4C10 A1g A2c GalN4C12 A1g A2d GalN4C14 A1g A2e GluN1C10 A1h A2c GluN1C12 A1h A2d GluN1C14 A1h A2e GluN2C8 A1i A2b GluN2C10 A1i A2c GluN2C12 A1i A2d GluN2C14 A1i A2e GluN3C6 A1j A2a GluN3C8 A1j A2b GluN3C10 A1j A2c GluN3C12 A1j A2d GluN3C14 A1j A2e GluN4C8 A1k A2b GluN4C10 A1k A2c GluN4C12 A1k A2d GluN4C14 A1k A2e TarN1C16 A1o A2f TarN2C16 A1b A2f TarN3C16 A1c A2f GalN2C10 A1q A2c GalN3C10 A1r A2c GalN2C12 A1q A2d GalN3C12 A1r A2d GalN2C14 A1q A2e GalN3C14 A1r A2e GalN2C16 A1q A2f GalN3C16 A1r A2f GluN2C10 A1t A2c GluN3C10 A1u A2c GluN1C12 A1s A2d GluN2C12 A1t A2d GluN3C12 A1u A2d GluN1C14 A1s A2e GluN2C14 A1t A2e GluN3C14 A1u A2e GluN1C16 A1s A2f GluN2C16 A1t A2f GluN3C16 A1u A2f; wherein: the poly(glycoamidoamine) is of the formula as shown in the table below: ##STR00464## ##STR00465## ##STR00466## the epoxide is of the formula as shown in the table below: ##STR00467## or a salt thereof.

22. The composition of claim 18, wherein the agent is a polynucleotide, small molecule, protein, or peptide.

23. The composition of claim 18, wherein the agent is a polynucleotide.

24. The composition of claim 23, wherein the polynucleotide is DNA.

25. The composition of claim 24, wherein the DNA is is single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, or viral DNA.

26. The composition of claim 23, wherein the polynucleotide is RNA.

27. The composition of claim 25, wherein the RNA is mRNA, siRNA, single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1A to 1C show exemplary expression levels of Factor VII (FVII) in C57BL/6 mice treated with FVII siRNA and a polymer described herein.

(2) FIG. 2. Illustration of particle formulation with cholesterol, DOPE, mPEG2000-DMG, and mRNA via a microfluidic based mixing device, and evaluation through intravenous delivery of luciferase mRNA. Scale bar is 100 nm.

(3) FIGS. 3A to 3E. mRNA delivery efficiency of nanoparticles of exemplary polymers described herein. FIG. 3A: Expression of EPO in mouse serum for the nanoparticles at a dose of 0.3 mg/kg of mRNA. Data shown is means.d. (n=3). Nanoparticles of TarN3C10 demonstrated EPO expression over one thousand fold higher than free mRNA. FIG. 3B: Biodistribution evaluated by luciferase expression in several organs. The TarN3C10-mRNA treated mice demonstrated one thousand fold higher luciferase expression in the liver and spleen compared to the group treated with free luciferase mRNA (normalized by tissue weight). Data shown is means.d. (n=5). FIG. 3C: Cryo-TEM of TarN3C10 without mRNA. FIG. 3D and FIG. 3E: Cryo-TEM of TarN3C10 nanoparticles formulated with mRNA. The TarN3C10 nanoparticles form round spherical objects (FIG. 3D), and the addition of mRNA leads to formation of more complex structures (FIG. 3E). Scale bar is 100 nm for all cryo-TEM images.

(4) FIG. 4. Histology images of select tissues (liver, spleen, kidney, heart, and lung) of mice (Scale bar=50 m). The mice were treated with PBS (control) or with TarN3C10 at 0.5 mg/kg at 24 hours or 48 hours. No histological abnormalities were observed in the treated tissues at either time.

(5) FIG. 5. Expression of EPO in mouse serum. Polymer TarN3C10 was formulated using two formulation methods: formulation 1 (polymer brush, DSPC, cholesterol, and mPEG2000-DMG), formulation 2 (polymer brush, DOPE, cholesterol, and mPEG2000-DMG). TarN3C10 nanoparticles with formulation 2 showed higher expression of EPO in comparison to formulation 1.

(6) FIG. 6. Cytokine induction of TarN3C10 nanoparticles at 24 and 48 hours compared with PBS control group.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

(7) The present disclosure provides brush-poly(glycoamidoamine)-lipids (PGALs) and uses thereof. In one aspect, described herein are polymers of any one of Formulae (I)-(IV), and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof. Also described herein are compositions including a polymer described herein and optionally an excipient. In certain embodiments, the compositions further include an agent (e.g., a polynucleotide (e.g., RNA or DNA), small molecule, peptide, or protein). The polymers and compositions have been found to be able to deliver effectively and efficiently an agent to a subject, tissue, or cell. In certain embodiments, the compositions are useful in delivering (e.g., selectively delivering) the agent to a subject, tissue (e.g., liver, spleen, or lung), or cell. The compositions (e.g., pharmaceutical compositions) may also be useful in treating and/or preventing a variety of diseases (e.g., genetic diseases, proliferative diseases, hematological diseases, neurological diseases, gastrointestinal diseases (e.g., liver diseases), spleen diseases, respiratory diseases (e.g., lung diseases), painful conditions, psychiatric disorders, musculoskeletal diseases, genitourinary diseases, and metabolic disorders) in a subject in need thereof. The PGALs described herein were shown to deliver erythropoietin (EPO) mRNA in mice. The PGALs did not show toxicity based on analysis of tissue histology, systemic cytokine levels, and liver enzyme chemistry. The PGALs are more potent than reported non-viral intravenous mRNA delivery systems.

(8) Polymers

(9) In one aspect, the present disclosure provides polymers of Formula (I):

(10) ##STR00037##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(11) X.sup.A is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.XA, N(R.sup.XA).sub.2, SR.sup.XA, C(NR.sup.XA)R.sup.XA, C(NR.sup.XA)OR.sup.XA, C(NR.sup.XA)N(R.sup.XA).sub.2, C(O)R.sup.XA, C(O)OR.sup.XA, or C(O)N(R.sup.XA).sub.2, wherein each instance of R.sup.XA is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XA are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

(12) each instance of Y.sup.A is independently O, S, or NR.sup.YA, wherein each instance of R.sup.YA is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(13) each instance of R.sup.A is independently hydrogen, a moiety of the formula:

(14) ##STR00038##
or a moiety of the formula:

(15) ##STR00039##
wherein: at least one instance of R.sup.A is of the formula:

(16) ##STR00040##
and each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; each instance of R.sup.A2 is independently hydrogen or substituted or unsubstituted alkyl; and each instance of R.sup.A3 is independently hydrogen or substituted or unsubstituted alkyl;

(17) each instance of a is 1, 2, 3, 4, or 5;

(18) each instance of k is 0, 1, 2, 3, 4, 5, or 6;

(19) each instance of u is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

(20) p is an integer between 1 and 1000, inclusive.

(21) In another aspect, the present disclosure provides polymers of Formula (I):

(22) ##STR00041##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(23) each instance of X.sup.A is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.XA, N(R.sup.XA).sub.2, SR.sup.XA, C(NR.sup.XA)R.sup.XA, C(NR.sup.XA)OR.sup.XA, C(NR.sup.XA)N(R.sup.XA).sub.2, C(O)R.sup.XA, C(O)OR.sup.XA, or C(O)N(R.sup.XA).sub.2, wherein each instance of R.sup.XA is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XA are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

(24) each instance of Y.sup.A is independently O, S, or NR.sup.YA, wherein each instance of R.sup.YA is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(25) each instance of R.sup.A is independently hydrogen, a moiety of the formula:

(26) ##STR00042##
or a moiety of the formula:

(27) ##STR00043##
wherein: at least one instance of R.sup.A is of the formula:

(28) ##STR00044##
and each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; each instance of R.sup.A2 is independently hydrogen or substituted or unsubstituted alkyl; and each instance of R.sup.A3 is independently hydrogen or substituted or unsubstituted alkyl;

(29) each instance of a is 1, 2, 3, 4, or 5;

(30) each instance of k is 0, 1, 2, 3, 4, 5, or 6;

(31) each instance of u is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

(32) p is an integer between 1 and 1000, inclusive.

(33) In another aspect, the present disclosure provides polymers of Formula (I):

(34) ##STR00045##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(35) each instance of Y.sup.A is independently O, S, or NR.sup.YA, wherein each instance of R.sup.YA is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(36) each instance of R.sup.A is independently hydrogen, a moiety of the formula:

(37) ##STR00046##
or a moiety of the formula:

(38) ##STR00047##
wherein: at least one instance of R.sup.A is of the formula:

(39) ##STR00048##
and each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; each instance of R.sup.A2 is independently hydrogen or substituted or unsubstituted alkyl; and each instance of R.sup.A3 is independently hydrogen or substituted or unsubstituted alkyl;

(40) each instance of a is 1, 2, 3, 4, or 5;

(41) each instance of k is 0, 1, 2, 3, 4, 5, or 6;

(42) each instance of u is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and p is an integer between 1 and 1000, inclusive.

(43) Any one of Formulae (I), (I), and (I) includes more than one hydroxyl moieties. In certain embodiments, all instances of the hydroxyl moieties are of the same configuration. In certain embodiments, at least two instances of the hydroxyl moieties are of different configurations. In certain embodiments, at least one instance of the hydroxyl moieties is of the R-configuration. In certain embodiments, at least one instance of the hydroxyl moieties is of the S-configuration.

(44) Formula (I) includes end group X.sup.A. In certain embodiments, X.sup.A is substituted alkyl. In certain embodiments, X.sup.A is unsubstituted alkyl. In certain embodiments, X.sup.A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.A is substituted C.sub.1-6 alkyl. In certain embodiments, X.sup.A is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, X.sup.A is CH.sub.3. In certain embodiments, X.sup.A is substituted methyl. In certain embodiments, X.sup.A is CH.sub.2F. In certain embodiments, X.sup.A is CHF.sub.2. In certain embodiments, X.sup.A is CF.sub.3. In certain embodiments, X.sup.A is ethyl. In certain embodiments, X.sup.A is propyl. In certain embodiments, X.sup.A is butyl. In certain embodiments, X.sup.A is pentyl. In certain embodiments, X.sup.A is hexyl. In certain embodiments, X.sup.A is halogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.A is substituted alkenyl. In certain embodiments, X.sup.A is unsubstituted alkenyl. In certain embodiments, X.sup.A is substituted alkynyl. In certain embodiments, X.sup.A is unsubstituted alkynyl. In certain embodiments, X.sup.A is substituted carbocyclyl. In certain embodiments, X.sup.A is unsubstituted carbocyclyl. In certain embodiments, X.sup.A is saturated carbocyclyl. In certain embodiments, X.sup.A is unsaturated carbocyclyl. In certain embodiments, X.sup.A is monocyclic carbocyclyl. In certain embodiments, X.sup.A is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, X.sup.A is substituted heterocyclyl. In certain embodiments, X.sup.A is unsubstituted heterocyclyl. In certain embodiments, X.sup.A is saturated heterocyclyl. In certain embodiments, X.sup.A is unsaturated heterocyclyl. In certain embodiments, X.sup.A is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, X.sup.A is monocyclic heterocyclyl. In certain embodiments, X.sup.A is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, X.sup.A is substituted aryl. In certain embodiments, X.sup.A is unsubstituted aryl. In certain embodiments, X.sup.A is 6- to 10-membered aryl. In certain embodiments, X.sup.A is substituted phenyl. In certain embodiments, X.sup.A is unsubstituted phenyl. In certain embodiments, X.sup.A is substituted heteroaryl. In certain embodiments, X.sup.A is unsubstituted heteroaryl. In certain embodiments, X.sup.A is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, X.sup.A is monocyclic heteroaryl. In certain embodiments, X.sup.A is 5-membered, monocyclic heteroaryl. In certain embodiments, X.sup.A is 6-membered, monocyclic heteroaryl. In certain embodiments, X.sup.A is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, X.sup.A is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, X.sup.A is OR.sup.XA. In certain embodiments, X.sup.A is OH. In certain embodiments, X.sup.A is OR.sup.XA, wherein R.sup.XA is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.A is OMe. In certain embodiments, X.sup.A is OEt, OPr, OBu, or OBn. In certain embodiments, X.sup.A is OPh. In certain embodiments, X.sup.A is SR.sup.XA. In certain embodiments, X.sup.A is SH. In certain embodiments, X.sup.A is SMe. In certain embodiments, X.sup.A is N(R.sup.XA).sub.2. In certain embodiments, X.sup.A is NH.sub.2. In certain embodiments, X.sup.A is NHMe. In certain embodiments, X.sup.A is NMe.sub.2. In certain embodiments, X.sup.A is OR.sup.XA or N(R.sup.XA).sub.2. In certain embodiments, X.sup.A is C(NR.sup.XA)R.sup.XA, C(NR.sup.XA)OR.sup.XA, or C(NR.sup.XA)N(R.sup.XA).sub.2. In certain embodiments, X.sup.A is C(O)R.sup.XA or C(O)OR.sup.XA. In certain embodiments, X.sup.A is C(O)N(R.sup.XA).sub.2. In certain embodiments, X.sup.A is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2.

(45) Formula (I) includes end groups X.sup.A. In certain embodiments, all instances of X.sup.A are the same. In certain embodiments, two instances of X.sup.A are not the same. In certain embodiments, at least one instance of X.sup.A is substituted alkyl. In certain embodiments, at least one instance of X.sup.A is unsubstituted alkyl. In certain embodiments, at least one instance of X.sup.A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.A is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.A is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of X.sup.A is CH.sub.3. In certain embodiments, at least one instance of X.sup.A is substituted methyl. In certain embodiments, at least one instance of X.sup.A is CH.sub.2F. In certain embodiments, at least one instance of X.sup.A is CHF.sub.2. In certain embodiments, at least one instance of X.sup.A is CF.sub.3. In certain embodiments, at least one instance of X.sup.A is ethyl. In certain embodiments, at least one instance of X.sup.A is propyl. In certain embodiments, at least one instance of X.sup.A is butyl. In certain embodiments, at least one instance of X.sup.A is pentyl. In certain embodiments, at least one instance of X.sup.A is hexyl. In certain embodiments, at least one instance of X.sup.A is halogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.A is substituted alkenyl. In certain embodiments, at least one instance of X.sup.A is unsubstituted alkenyl. In certain embodiments, at least one instance of X.sup.A is substituted alkynyl. In certain embodiments, at least one instance of X.sup.A is unsubstituted alkynyl. In certain embodiments, at least one instance of X.sup.A is substituted carbocyclyl. In certain embodiments, at least one instance of X.sup.A is unsubstituted carbocyclyl. In certain embodiments, at least one instance of X.sup.A is saturated carbocyclyl. In certain embodiments, at least one instance of X.sup.A is unsaturated carbocyclyl. In certain embodiments, at least one instance of X.sup.A is monocyclic carbocyclyl. In certain embodiments, at least one instance of X.sup.A is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of X.sup.A is substituted heterocyclyl. In certain embodiments, at least one instance of X.sup.A is unsubstituted heterocyclyl. In certain embodiments, at least one instance of X.sup.A is saturated heterocyclyl. In certain embodiments, at least one instance of X.sup.A is unsaturated heterocyclyl. In certain embodiments, at least one instance of X.sup.A is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of X.sup.A is monocyclic heterocyclyl. In certain embodiments, at least one instance of X.sup.A is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of X.sup.A is substituted aryl. In certain embodiments, at least one instance of X.sup.A is unsubstituted aryl. In certain embodiments, at least one instance of X.sup.A is 6- to 10-membered aryl. In certain embodiments, at least one instance of X.sup.A is substituted phenyl. In certain embodiments, at least one instance of X.sup.A is unsubstituted phenyl. In certain embodiments, at least one instance of X.sup.A is substituted heteroaryl. In certain embodiments, at least one instance of X.sup.A is unsubstituted heteroaryl. In certain embodiments, at least one instance of X.sup.A is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of X.sup.A is monocyclic heteroaryl. In certain embodiments, at least one instance of X.sup.A is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of X.sup.A is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of X.sup.A is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of X.sup.A is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of X.sup.A is OR.sup.XA. In certain embodiments, at least one instance of X.sup.A is OH. In certain embodiments, at least one instance of X.sup.A is OR.sup.XA, wherein R.sup.XA is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.A is OMe. In certain embodiments, at least one instance of X.sup.A is OEt, OPr, OBu, or OBn. In certain embodiments, at least one instance of X.sup.A is OPh. In certain embodiments, at least one instance of X.sup.A is SR.sup.XA. In certain embodiments, at least one instance of X.sup.A is SH. In certain embodiments, at least one instance of X.sup.A is SMe. In certain embodiments, at least one instance of X.sup.A is N(R.sup.XA).sub.2. In certain embodiments, at least one instance of X.sup.A is NH.sub.2. In certain embodiments, at least one instance of X.sup.A is NHMe. In certain embodiments, at least one instance of X.sup.A is NMe.sub.2. In certain embodiments, at least one instance of X.sup.A is OR.sup.XA or N(R.sup.XA).sub.2. In certain embodiments, at least one instance of X.sup.A is C(NR.sup.XA)R.sup.XA, C(NR.sup.XA)OR.sup.XA, or C(NR.sup.XA)N(R.sup.XA).sub.2. In certain embodiments, at least one instance of X.sup.A is C(O)R.sup.XA or C(O)OR.sup.XA. In certain embodiments, at least one instance of X.sup.A is C(O)N(R.sup.XA).sub.2. In certain embodiments, at least one instance of X.sup.A is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2.

(46) For any of the X.sup.A that include an R.sup.XA moiety described herein, any of the following embodiments for R.sup.XA may be applicable. In certain embodiments, R.sup.XA is H. In certain embodiments, R.sup.XA is substituted acyl. In certain embodiments, R.sup.XA is unsubstituted acyl. In certain embodiments, R.sup.XA is acetyl. In certain embodiments, R.sup.XA is substituted alkyl. In certain embodiments, R.sup.XA is unsubstituted alkyl. In certain embodiments, R.sup.XA is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.XA is methyl. In certain embodiments, R.sup.XA is ethyl. In certain embodiments, R.sup.XA is propyl. In certain embodiments, R.sup.XA is butyl. In certain embodiments, R.sup.XA is pentyl. In certain embodiments, R.sup.XA is hexyl. In certain embodiments, R.sup.XA is substituted alkenyl. In certain embodiments, R.sup.XA is unsubstituted alkenyl. In certain embodiments, R.sup.XA is substituted alkynyl. In certain embodiments, R.sup.XA is unsubstituted alkynyl. In certain embodiments, R.sup.XA is substituted or unsubstituted carbocyclyl. In certain embodiments, R.sup.XA is saturated carbocyclyl. In certain embodiments, R.sup.XA is unsaturated carbocyclyl. In certain embodiments, R.sup.XA is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.XA is substituted or unsubstituted heterocyclyl. In certain embodiments, R.sup.XA is saturated heterocyclyl. In certain embodiments, R.sup.XA is unsaturated heterocyclyl. In certain embodiments, R.sup.XA is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.XA is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.XA is substituted or unsubstituted aryl. In certain embodiments, R.sup.XA is 6- to 10-membered aryl. In certain embodiments, R.sup.XA is monocyclic aryl. In certain embodiments, R.sup.XA is substituted phenyl. In certain embodiments, R.sup.XA is unsubstituted phenyl. In certain embodiments, R.sup.XA is bicyclic aryl. In certain embodiments, R.sup.XA is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.XA is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.XA is monocyclic heteroaryl. In certain embodiments, R.sup.XA is 5- or 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.XA is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, R.sup.XA is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, R.sup.XA is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.XA is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.XA is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.XA is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.XA is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two instances of R.sup.XA are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.XA are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.XA are joined to form a heterocyclic ring, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.XA are joined to form a 3- to 7-membered, monocyclic heterocyclic ring. In certain embodiments, two instances of R.sup.XA are joined to form a substituted or unsubstituted heteroaryl ring. In certain embodiments, two instances of R.sup.XA are joined to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms of the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.

(47) Any one of Formulae (I), (I), and (I) includes Y.sup.A moieties. In certain embodiments, all instances of Y.sup.A are the same. In certain embodiments, at least two instances of Y.sup.A are different from each other. In certain embodiments, at least one instance of Y.sup.A is O. In certain embodiments, each instance of Y.sup.A is O. In certain embodiments, at least one instance of Y.sup.A is S. In certain embodiments, at least one instance of Y.sup.A is NR.sup.YA. In certain embodiments, at least one instance of Y.sup.A is NH. In certain embodiments, at least one instance of Y.sup.A is N(substituted or unsubstituted C.sub.1-6 alkyl, e.g., methyl).

(48) In certain embodiments, all instances of R.sup.YA are the same. In certain embodiments, at least two instances of R.sup.YA are different from each other. In certain embodiments, at least one instance of R.sup.YA is H. In certain embodiments, at least one instance of R.sup.YA is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.YA is methyl. In certain embodiments, at least one instance of R.sup.YA is ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, at least one instance of R.sup.YA is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

(49) Any one of Formulae (I), (I), and (I) includes substituents R.sup.A. In certain embodiments, at least about 10%, at least about 20%, at least about 30%, or at least about 40% of the total instances of R.sup.A are the same. In certain embodiments, at least about 50% of the total instances of R.sup.A are the same. In certain embodiments, at least about 60% of the total instances of R.sup.A are the same. In certain embodiments, at least about 70% of the total instances of R.sup.A are the same. In certain embodiments, at least about 80% of the total instances of R.sup.A are the same. In certain embodiments, at least about 90% of the total instances of R.sup.A are the same. In certain embodiments, at least about 95% of the total instances of R.sup.A are the same. In certain embodiments, all instances of R.sup.A are the same. In certain embodiments, at least two instances of R.sup.A are different from each other. In certain embodiments, at least one instance of R.sup.A is H. In certain embodiments, at least one instance of R.sup.A is of the formula:

(50) ##STR00049##
In certain embodiments, at least one instance of R.sup.A is of the formula:

(51) ##STR00050##
In certain embodiments, at least one instance of R.sup.A is of the formula:

(52) ##STR00051##
In certain embodiments, at least one instance of R.sup.A is of the formula:

(53) ##STR00052##
In certain embodiments, at least one instance of R.sup.A is of the formula:

(54) ##STR00053##
In certain embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the total instances of R.sup.A are independently of the formula:

(55) ##STR00054##
In certain embodiments, all instances of R.sup.A are independently of the formula:

(56) ##STR00055##
In certain embodiments, at least one instance of R.sup.A is of the formula:

(57) ##STR00056##
In certain embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the total instances of R.sup.A are independently of the formula:

(58) ##STR00057##
In certain embodiments, all instances of R.sup.A are independently of the formula:

(59) ##STR00058##
In certain embodiments, each instance of R.sup.A is independently H, a moiety of the formula:

(60) ##STR00059##
or a moiety of the formula:

(61) ##STR00060##
wherein: at least one instance of R.sup.A is of the formula:

(62) ##STR00061##
and each instance of R.sup.A1 is independently unsubstituted C.sub.4-18 alkyl.

(63) Each instance of R.sup.A in any one of Formulae (I), (I), and (I) includes one or more substituents R.sup.A1. In certain embodiments, all instances of R.sup.A1 are the same. In certain embodiments, all instances of R.sup.A1 that are not hydrogen are the same. In certain embodiments, at least two instances of R.sup.A1 are different from each other. In certain embodiments, at least one instance of R.sup.A1 is H. In certain embodiments, each instance of R.sup.A1 is H. In certain embodiments, at least one instance of R.sup.A1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkyl. In certain embodiments, each instance of R.sup.A1 is independently substituted or unsubstituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.A1 is substituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.A1 is a moiety shown in Table 2. In certain embodiments, each instance of R.sup.A1 is independently a moiety shown in Table 2. In certain embodiments, each instance of R.sup.A1 is a moiety shown in Table 2. In certain embodiments, at least one instance of R.sup.A1 is C.sub.1-30 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.A1 is C.sub.1-30 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.A1 is C.sub.1-30 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.A1 is a moiety shown in Table 1. In certain embodiments, each instance of R.sup.A1 is independently a moiety shown in Table 1. In certain embodiments, each instance of R.sup.A1 is a moiety shown in Table 1. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted and unbranched C.sub.1-30 alkyl. In certain embodiments, each instance of R.sup.A1 is independently substituted or unsubstituted C.sub.4-22 alkyl (e.g., substituted or unsubstituted C.sub.4-18 alkyl). In certain embodiments, at least one instance of R.sup.A1 is substituted C.sub.4-18 alkyl. In certain embodiments, at least one instance of R.sup.A1 is C.sub.4-18 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.A1 is C.sub.4-18 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.A1 is C.sub.4-18 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted C.sub.4-18 alkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted and unbranched C.sub.4-18 alkyl. In certain embodiments, each instance of R.sup.A1 is independently substituted or unsubstituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.A1 is substituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.A1 is C.sub.6-14 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.A1 is C.sub.6-14 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.A1 is C.sub.6-14 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted and unbranched C.sub.6-14 alkyl. In certain embodiments, each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25. In certain embodiments, each instance of R.sup.A1 is n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25.

(64) TABLE-US-00001 TABLE 1 Exemplary unsubstituted alkyl moieties. 0

(65) TABLE-US-00002 TABLE 2 Exemplary substituted alkyl moieties. 0 0

(66) In certain embodiments, at least one instance of R.sup.A1 is substituted alkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkenyl. In certain embodiments, each instance of R.sup.A1 is independently substituted or unsubstituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is substituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is C.sub.2-30 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.A1 is C.sub.2-30 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.A1 is C.sub.2-30 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is a moiety shown in Table 3. In certain embodiments, each instance of R.sup.A1 is independently a moiety shown in Table 3. In certain embodiments, each instance of R.sup.A1 is a moiety shown in Table 3. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted and unbranched C.sub.2-30 alkenyl. In certain embodiments, each instance of R.sup.A1 is independently substituted or unsubstituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is substituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is C.sub.4-18 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.A1 is C.sub.4-18 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.A1 is C.sub.4-18 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted and unbranched C.sub.4-18 alkenyl. In certain embodiments, each instance of R.sup.A1 is independently substituted or unsubstituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is substituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is C.sub.6-14 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.A1 is C.sub.6-14 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.A1 is C.sub.6-14 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted and unbranched C.sub.6-14 alkenyl.

(67) TABLE-US-00003 TABLE 3 Exemplary unsubstituted alkenyl moieties. 00 01 02 03 04 05 06 07 08 09 0 (CH.sub.2).sub.7CHCH(CH.sub.2).sub.3CH.sub.3 (CH.sub.2).sub.7CHCH(CH.sub.2).sub.5CH.sub.3 (CH.sub.2).sub.4CHCH(CH.sub.2).sub.8CH.sub.3 (CH.sub.2).sub.7CHCH(CH.sub.2).sub.7CH.sub.3 (CH.sub.2).sub.7CHCHCH.sub.2CHCH(CH.sub.2).sub.4CH.sub.3 (CH.sub.2).sub.7CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CH.sub.3 (CH.sub.2).sub.3CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCH(CH.sub.2).sub.4CH.sub.3 (CH.sub.2).sub.3CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CH.sub.3 (CH.sub.2).sub.11CHCH(CH.sub.2).sub.7CH.sub.3 (CH.sub.2).sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CH.sub.3 0

(68) In certain embodiments, all instances of R.sup.A2 are the same. In certain embodiments, at least two instances of R.sup.A2 are different from each other. In certain embodiments, at least one instance of R.sup.A2 is H. In certain embodiments, each instance of R.sup.A2 is H. In certain embodiments, at least one instance of R.sup.A2 is substituted alkyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, both instances of R.sup.A2 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A2 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A2 is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.A2 is CH.sub.3. In certain embodiments, at least one instance of R.sup.A2 is substituted methyl. In certain embodiments, at least one instance of R.sup.A2 is CH.sub.2F, CHF.sub.2, or CF.sub.3. In certain embodiments, at least one instance of R.sup.A2 is ethyl, propyl, butyl, pentyl, or hexyl.

(69) In certain embodiments, all instances of R.sup.A3 are the same. In certain embodiments, at least two instances of R.sup.A3 are different from each other. In certain embodiments, at least one instance of R.sup.A3 is H. In certain embodiments, each instance of R.sup.A3 is H. In certain embodiments, at least one instance of R.sup.A3 is substituted alkyl. In certain embodiments, at least one instance of R.sup.A3 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, both instances of R.sup.A3 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A3 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A3 is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.A3 is CH.sub.3. In certain embodiments, at least one instance of R.sup.A3 is substituted methyl. In certain embodiments, at least one instance of R.sup.A3 is CH.sub.2F, CHF.sub.2, or CF.sub.3. In certain embodiments, at least one instance of R.sup.A3 is ethyl, propyl, butyl, pentyl, or hexyl.

(70) In certain embodiments, all instances of R.sup.A2 and R.sup.A3 are H.

(71) In certain embodiments, each instance of a is 1. In certain embodiments, each instance of a is 2. In certain embodiments, each instance of a is 3. In certain embodiments, each instance of a is 4. In certain embodiments, each instance of a is 5.

(72) In certain embodiments, each instance of k is 0. In certain embodiments, each instance of k is 1. In certain embodiments, each instance of k is 2. In certain embodiments, each instance of k is 3. In certain embodiments, each instance of k is 4. In certain embodiments, each instance of k is 5. In certain embodiments, each instance of k is 6.

(73) In certain embodiments, each instance of u is 1. In certain embodiments, each instance of u is 2. In certain embodiments, each instance of u is 3. In certain embodiments, each instance of u is 4. In certain embodiments, each instance of u is 5. In certain embodiments, each instance of u is 6. In certain embodiments, each instance of u is 7. In certain embodiments, each instance of u is 8. In certain embodiments, each instance of u is 9. In certain embodiments, each instance of u is 10.

(74) In certain embodiments, p is an integer between 1 and 1000, inclusive. In certain embodiments, p is an integer between 1 and 300, inclusive. In certain embodiments, p is an integer between 1 and 100, inclusive. In certain embodiments, p is an integer between 1 and 70, inclusive. In certain embodiments, p is an integer between 1 and 50, inclusive. In certain embodiments, p is an integer between 1 and 30, inclusive. In certain embodiments, p is an integer between 5 and 30, inclusive. In certain embodiments, p is an integer between 10 and 20, inclusive. In certain embodiments, p is an integer between 1 and 15, inclusive. In certain embodiments, p is an integer between 5 and 15, inclusive. In certain embodiments, p is 10 or 11.

(75) In certain embodiments, the polymer of Formula (I) is of the formula:

(76) ##STR00129##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(77) In certain embodiments, the polymer of Formula (I) is of the formula:

(78) ##STR00130##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(79) In certain embodiments, the polymer of Formula (I) is of the formula:

(80) ##STR00131##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(81) In certain embodiments, the polymer of Formula (I) is of the formula:

(82) ##STR00132##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(83) In certain embodiments, the polymer of Formula (I) is of the formula:

(84) ##STR00133##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(85) ##STR00134##
or a moiety of the formula:

(86) ##STR00135##
wherein: at least one instance of R.sup.A is of the formula:

(87) ##STR00136##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(88) In certain embodiments, the polymer of Formula (I) is of the formula:

(89) ##STR00137##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(90) ##STR00138##
or a moiety of the formula:

(91) ##STR00139##
wherein: at least one instance of R.sup.A is of the formula:

(92) ##STR00140##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(93) In certain embodiments, the polymer of Formula (I) is of the formula:

(94) ##STR00141##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(95) ##STR00142##
or a moiety of the formula:

(96) ##STR00143##
wherein: at least one instance of R.sup.A is of the formula:

(97) ##STR00144##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(98) In certain embodiments, the polymer of Formula (I) is of the formula:

(99) ##STR00145##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(100) ##STR00146##
or a moiety of the formula:

(101) ##STR00147##
wherein: at least one instance of R.sup.A is of the formula:

(102) ##STR00148##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(103) In certain embodiments, the polymer of Formula (I) is of the formula:

(104) ##STR00149##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(105) In certain embodiments, the polymer of Formula (I) is of the formula:

(106) ##STR00150##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(107) In certain embodiments, the polymer of Formula (I) is of the formula:

(108) ##STR00151##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(109) In certain embodiments, the polymer of Formula (I) is of the formula:

(110) ##STR00152##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(111) ##STR00153##
or a moiety of the formula:

(112) ##STR00154##
wherein: at least one instance of R.sup.A is of the formula:

(113) ##STR00155##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(114) In certain embodiments, the polymer of Formula (I) is of the formula:

(115) ##STR00156##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(116) ##STR00157##
or a moiety of the formula:

(117) ##STR00158##
wherein: at least one instance of R.sup.A is of the formula:

(118) ##STR00159##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(119) In certain embodiments, the polymer of Formula (I) is of the formula:

(120) ##STR00160##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(121) ##STR00161##
or a moiety of the formula:

(122) ##STR00162##
wherein: at least one instance of R.sup.A is of the formula:

(123) ##STR00163##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(124) In certain embodiments, the polymer of Formula (I) is of the formula:

(125) ##STR00164##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(126) In certain embodiments, the polymer of Formula (I) is of the formula:

(127) ##STR00165##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(128) In certain embodiments, the polymer of Formula (I) is of the formula:

(129) ##STR00166##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(130) ##STR00167##
or a moiety of the formula:

(131) ##STR00168##
wherein: at least one instance of R.sup.A is of the formula:

(132) ##STR00169##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(133) In certain embodiments, the polymer of Formula (I) is of the formula:

(134) ##STR00170##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(135) ##STR00171##
or a moiety of the formula:

(136) ##STR00172##
wherein: at least one instance of R.sup.A is of the formula:

(137) ##STR00173##
and each instance of R.sup.A1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(138) In certain embodiments, the polymer of Formula (I) is of the formula:

(139) ##STR00174##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(140) ##STR00175##
or a moiety of the formula:

(141) ##STR00176##
wherein: at least one instance of R.sup.A is of the formula:

(142) ##STR00177##
and each instance of R.sup.A1 is n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(143) In certain embodiments, the polymer of Formula (I) is of the formula:

(144) ##STR00178##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of R.sup.A is independently H, a moiety of the formula:

(145) ##STR00179##
or a moiety of the formula:

(146) ##STR00180##
wherein: at least one instance of R.sup.A is of the formula:

(147) ##STR00181##
and each instance of R.sup.A1 is n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(148) In certain embodiments, the polymer of Formula (I) is of the formula:

(149) ##STR00182##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof, wherein each instance of C.sub.8H.sub.17 is n-C.sub.8H.sub.17.

(150) In certain embodiments, the polymer of Formula (I) is of the formula:

(151) ##STR00183##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(152) In certain embodiments, the polymer of Formula (I) is of the formula:

(153) ##STR00184##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(154) In certain embodiments, the polymer of Formula (I) is of the formula:

(155) ##STR00185##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(156) In certain embodiments, the polymer of Formula (I) is of the formula:

(157) ##STR00186##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(158) In certain embodiments, the polymer of Formula (I) is of the formula:

(159) ##STR00187##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(160) In certain embodiments, the polymer of Formula (I) is of the formula:

(161) ##STR00188##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(162) In certain embodiments, the polymer of Formula (I) is of the formula:

(163) ##STR00189##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(164) In certain embodiments, the polymer of Formula (I) is of the formula:

(165) ##STR00190##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(166) In certain embodiments, the polymer of Formula (I) is of the formula:

(167) ##STR00191##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(168) In certain embodiments, the polymer of Formula (I) is of the formula:

(169) ##STR00192##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(170) In certain embodiments, the polymer of Formula (I) is of the formula:

(171) ##STR00193##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(172) In certain embodiments, the polymer of Formula (I) is of the formula:

(173) ##STR00194##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(174) In certain embodiments, the polymer of Formula (I) is of the formula:

(175) ##STR00195##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(176) In certain embodiments, the polymer of Formula (I) is of the formula:

(177) ##STR00196##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(178) In certain embodiments, the polymer of Formula (I) is of the formula:

(179) ##STR00197##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(180) In certain embodiments, the polymer of Formula (I) is of the formula:

(181) ##STR00198##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(182) In certain embodiments, the polymer of Formula (I) is of the formula:

(183) ##STR00199##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(184) In certain embodiments, the polymer of Formula (I) is of the formula:

(185) ##STR00200##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(186) In another aspect, the present disclosure provides polymers of Formula (II):

(187) ##STR00201##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(188) X.sup.B is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.XB, N(R.sup.XB).sub.2, SR.sup.XB, CN, SCN, C(NR.sup.XB)R.sup.XB, C(NR.sup.XB)OR.sup.XB, C(NR.sup.XB)N(R.sup.XB).sub.2, C(O)R.sup.XB, C(O)OR.sup.XB, or C(O)N(R.sup.XB).sub.2, NO.sub.2, NR.sup.XBC(O)R.sup.XB, NR.sup.XBC(O)OR.sup.XB, NR.sup.XBC(O)N(R.sup.XB).sub.2, OC(O)R.sup.XB, OC(O)OR.sup.XB, or OC(O)N(R.sup.XB).sub.2, wherein each instance of R.sup.XB is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XB are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

(189) each instance of Y.sup.B is independently O, S, or NR.sup.YB, wherein each instance of R.sup.YB is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(190) each instance of R.sup.B is independently hydrogen or a moiety of the formula:

(191) ##STR00202##
wherein: at least one instance of R.sup.B is of the formula:

(192) ##STR00203##
and each instance of R.sup.B1 is independently substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;

(193) each instance of b is 1, 2, 3, 4, or 5;

(194) each instance of m is 0, 1, 2, 3, 4, 5, or 6;

(195) each instance of v is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

(196) q is an integer between 1 and 1000, inclusive.

(197) In another aspect, the present disclosure provides polymers of Formula (II):

(198) ##STR00204##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(199) each instance of X.sup.B is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.B, N(R.sup.XB).sub.2, SR.sup.XB, CN, SCN, C(NR.sup.XB)R.sup.XB, C(NR.sup.XB)OR.sup.XB, C(NR.sup.XB)N(R.sup.XB).sub.2, C(O)R.sup.XB, C(O)OR.sup.XB, or C(O)N(R.sup.XB).sub.2, NO.sub.2, NR.sup.XBC(O)R.sup.XB, NR.sup.XBC(O)OR.sup.XB, NR.sup.XBC(O)N(R.sup.XB).sub.2, OC(O)R.sup.XB, OC(O)OR.sup.XB, or OC(O)N(R.sup.XB).sub.2, wherein each instance of R.sup.XB is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XB are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

(200) each instance of Y.sup.B is independently O, S, or NR.sup.YB, wherein each instance of R.sup.YB is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(201) each instance of R.sup.B is independently hydrogen or a moiety of the formula:

(202) ##STR00205##
wherein: at least one instance of R.sup.B is of the formula:

(203) ##STR00206##
and each instance of R.sup.B1 is independently substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;

(204) each instance of b is 1, 2, 3, 4, or 5;

(205) each instance of m is 0, 1, 2, 3, 4, 5, or 6;

(206) each instance of v is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

(207) q is an integer between 1 and 1000, inclusive.

(208) In another aspect, the present disclosure provides polymers of Formula (II):

(209) ##STR00207##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(210) each instance of Y.sup.B is independently O, S, or NR.sup.YB, wherein each instance of R.sup.YB is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(211) each instance of R.sup.B is independently hydrogen or a moiety of the formula:

(212) ##STR00208##
wherein: at least one instance of R.sup.B is of the formula:

(213) ##STR00209##
and each instance of R.sup.B1 is independently substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;

(214) each instance of b is 1, 2, 3, 4, or 5;

(215) each instance of m is 0, 1, 2, 3, 4, 5, or 6;

(216) each instance of v is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

(217) q is an integer between 1 and 1000, inclusive.

(218) Formula (II) includes end group X.sup.B. In certain embodiments, X.sup.B is substituted alkyl. In certain embodiments, X.sup.B is unsubstituted alkyl. In certain embodiments, X.sup.B is unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.B is substituted C.sub.1-6 alkyl. In certain embodiments, X.sup.B is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, X.sup.B is CH.sub.3. In certain embodiments, X.sup.B is substituted methyl. In certain embodiments, X.sup.B is CH.sub.2F. In certain embodiments, X.sup.B is CHF.sub.2. In certain embodiments, X.sup.B is CF.sub.3. In certain embodiments, X.sup.B is ethyl. In certain embodiments, X.sup.B is propyl. In certain embodiments, X.sup.B is butyl. In certain embodiments, X.sup.B is pentyl. In certain embodiments, X.sup.B is hexyl. In certain embodiments, X.sup.B is halogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.B is substituted alkenyl. In certain embodiments, X.sup.B is unsubstituted alkenyl. In certain embodiments, X.sup.B is substituted alkynyl. In certain embodiments, X.sup.B is unsubstituted alkynyl. In certain embodiments, X.sup.B is substituted carbocyclyl. In certain embodiments, X.sup.B is unsubstituted carbocyclyl. In certain embodiments, X.sup.B is saturated carbocyclyl. In certain embodiments, X.sup.B is unsaturated carbocyclyl. In certain embodiments, X.sup.B is monocyclic carbocyclyl. In certain embodiments, X.sup.B is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, X.sup.B is substituted heterocyclyl. In certain embodiments, X.sup.B is unsubstituted heterocyclyl. In certain embodiments, X.sup.B is saturated heterocyclyl. In certain embodiments, X.sup.B is unsaturated heterocyclyl. In certain embodiments, X.sup.B is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, X.sup.B is monocyclic heterocyclyl. In certain embodiments, X.sup.B is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, X.sup.B is substituted aryl. In certain embodiments, X.sup.B is unsubstituted aryl. In certain embodiments, X.sup.B is 6- to 10-membered aryl. In certain embodiments, X.sup.B is substituted phenyl. In certain embodiments, X.sup.B is unsubstituted phenyl. In certain embodiments, X.sup.B is substituted heteroaryl. In certain embodiments, X.sup.B is unsubstituted heteroaryl. In certain embodiments, X.sup.B is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, X.sup.B is monocyclic heteroaryl. In certain embodiments, X.sup.B is 5-membered, monocyclic heteroaryl. In certain embodiments, X.sup.B is 6-membered, monocyclic heteroaryl. In certain embodiments, X.sup.B is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, X.sup.B is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, X.sup.B is OR.sup.XB. In certain embodiments, X.sup.B is OH. In certain embodiments, X.sup.B is OR.sup.XB, wherein R.sup.XB is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.B is OMe. In certain embodiments, X.sup.B is OEt, OPr, OBu, or OBn. In certain embodiments, X.sup.B is OPh. In certain embodiments, X.sup.B is SR.sup.XB. In certain embodiments, X.sup.B is SH. In certain embodiments, X.sup.B is SMe. In certain embodiments, X.sup.B is N(R.sup.XB).sub.2. In certain embodiments, X.sup.B is NH.sub.2. In certain embodiments, X.sup.B is NHMe. In certain embodiments, X.sup.B is NMe.sub.2. In certain embodiments, X.sup.B is OR.sup.XB or N(R.sup.XB).sub.2. In certain embodiments, X.sup.B is C(NR.sup.XB)R.sup.XB, C(NR.sup.XB)OR.sup.XB, or C(NR.sup.XB)N(R.sup.XB).sub.2. In certain embodiments, X.sup.B is C(O)R.sup.XB or C(O)OR.sup.XB. In certain embodiments, X.sup.B is C(O)N(R.sup.XB).sub.2. In certain embodiments, X.sup.B is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2.

(219) Formula (II) includes end groups X.sup.B. In certain embodiments, all instances of X.sup.B are the same. In certain embodiments, two instances of X.sup.B are not the same. In certain embodiments, at least one instance of X.sup.B is substituted alkyl. In certain embodiments, at least one instance of X.sup.B is unsubstituted alkyl. In certain embodiments, at least one instance of X.sup.B is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.B is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.B is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of X.sup.B is CH.sub.3. In certain embodiments, at least one instance of X.sup.B is substituted methyl. In certain embodiments, at least one instance of X.sup.B is CH.sub.2F. In certain embodiments, at least one instance of X.sup.B is CHF.sub.2. In certain embodiments, at least one instance of X.sup.B is CF.sub.3. In certain embodiments, at least one instance of X.sup.B is ethyl. In certain embodiments, at least one instance of X.sup.B is propyl. In certain embodiments, at least one instance of X.sup.B is butyl. In certain embodiments, at least one instance of X.sup.B is pentyl. In certain embodiments, at least one instance of X.sup.B is hexyl. In certain embodiments, at least one instance of X.sup.B is halogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.B is substituted alkenyl. In certain embodiments, at least one instance of X.sup.B is unsubstituted alkenyl. In certain embodiments, at least one instance of X.sup.B is substituted alkynyl. In certain embodiments, at least one instance of X.sup.B is unsubstituted alkynyl. In certain embodiments, at least one instance of X.sup.B is substituted carbocyclyl. In certain embodiments, at least one instance of X.sup.B is unsubstituted carbocyclyl. In certain embodiments, at least one instance of X.sup.B is saturated carbocyclyl. In certain embodiments, at least one instance of X.sup.B is unsaturated carbocyclyl. In certain embodiments, at least one instance of X.sup.B is monocyclic carbocyclyl. In certain embodiments, at least one instance of X.sup.B is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of X.sup.B is substituted heterocyclyl. In certain embodiments, at least one instance of X.sup.B is unsubstituted heterocyclyl. In certain embodiments, at least one instance of X.sup.B is saturated heterocyclyl. In certain embodiments, at least one instance of X.sup.B is unsaturated heterocyclyl. In certain embodiments, at least one instance of X.sup.B is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of X.sup.B is monocyclic heterocyclyl. In certain embodiments, at least one instance of X.sup.B is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of X.sup.B is substituted aryl. In certain embodiments, at least one instance of X.sup.B is unsubstituted aryl. In certain embodiments, at least one instance of X.sup.B is 6- to 10-membered aryl. In certain embodiments, at least one instance of X.sup.B is substituted phenyl. In certain embodiments, at least one instance of X.sup.B is unsubstituted phenyl. In certain embodiments, at least one instance of X.sup.B is substituted heteroaryl. In certain embodiments, at least one instance of X.sup.B is unsubstituted heteroaryl. In certain embodiments, at least one instance of X.sup.B is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of X.sup.B is monocyclic heteroaryl. In certain embodiments, at least one instance of X.sup.B is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of X.sup.B is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of X.sup.B is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of X.sup.B is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of X.sup.B is OR.sup.B. In certain embodiments, at least one instance of X.sup.B is OH. In certain embodiments, at least one instance of X.sup.B is OR.sup.XB, wherein R.sup.XB is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, at least one instance of X.sup.B is OMe. In certain embodiments, at least one instance of X.sup.B is OEt, OPr, OBu, or OBn. In certain embodiments, at least one instance of X.sup.B is OPh. In certain embodiments, at least one instance of X.sup.B is SR.sup.XB. In certain embodiments, at least one instance of X.sup.B is SH. In certain embodiments, at least one instance of X.sup.B is SMe. In certain embodiments, at least one instance of X.sup.B is N(R.sup.XB).sub.2. In certain embodiments, at least one instance of X.sup.B is NH.sub.2. In certain embodiments, at least one instance of X.sup.B is NHMe. In certain embodiments, at least one instance of X.sup.B is NMe.sub.2. In certain embodiments, at least one instance of X.sup.B is OR.sup.XB or N(R.sup.XB).sub.2. In certain embodiments, at least one instance of X.sup.B is C(NR.sup.XB)R.sup.XB, C(NR.sup.XB)OR.sup.XB, or C(NR.sup.XB)N(R.sup.XB).sub.2. In certain embodiments, at least one instance of X.sup.B is C(O)R.sup.XB or C(O)OR.sup.XB. In certain embodiments, at least one instance of X.sup.B is C(O)N(R.sup.XB).sub.2. In certain embodiments, at least one instance of X.sup.B is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2.

(220) For any of the X.sup.B that include an R.sup.XB moiety described herein, any of the following embodiments for R.sup.XB may be applicable. In certain embodiments, R.sup.XB is H. In certain embodiments, R.sup.XB is substituted acyl. In certain embodiments, R.sup.XB is unsubstituted acyl. In certain embodiments, R.sup.XB is acetyl. In certain embodiments, R.sup.XB is substituted alkyl. In certain embodiments, R.sup.XB is unsubstituted alkyl. In certain embodiments, R.sup.XB is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.XB is methyl. In certain embodiments, R.sup.XB is ethyl. In certain embodiments, R.sup.XB is propyl. In certain embodiments, R.sup.XB is butyl. In certain embodiments, R.sup.XB is pentyl. In certain embodiments, R.sup.XB is hexyl. In certain embodiments, R.sup.XB is substituted alkenyl. In certain embodiments, R.sup.XB is unsubstituted alkenyl. In certain embodiments, R.sup.XB is substituted alkynyl. In certain embodiments, R.sup.XB is unsubstituted alkynyl. In certain embodiments, R.sup.XB is substituted or unsubstituted carbocyclyl. In certain embodiments, R.sup.XB is saturated carbocyclyl. In certain embodiments, R.sup.XB is unsaturated carbocyclyl. In certain embodiments, R.sup.XB is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.XB is substituted or unsubstituted heterocyclyl. In certain embodiments, R.sup.XB is saturated heterocyclyl. In certain embodiments, R.sup.XB is unsaturated heterocyclyl. In certain embodiments, R.sup.XB is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.XB is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.XB is substituted or unsubstituted aryl. In certain embodiments, R.sup.XB is 6- to 10-membered aryl. In certain embodiments, R.sup.XB is monocyclic aryl. In certain embodiments, R.sup.XB is substituted phenyl. In certain embodiments, R.sup.XB is unsubstituted phenyl. In certain embodiments, R.sup.XB is bicyclic aryl. In certain embodiments, R.sup.XB is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.XB is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.XB is monocyclic heteroaryl. In certain embodiments, R.sup.XB is 5- or 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.XB is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, R.sup.XB is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, R.sup.XB is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.XB is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.XB is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.XB is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.XB is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two instances of R.sup.XB are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.XB are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.XB are joined to form a heterocyclic ring, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.XB are joined to form a 3- to 7-membered, monocyclic heterocyclic ring. In certain embodiments, two instances of R.sup.XB are joined to form a substituted or unsubstituted heteroaryl ring. In certain embodiments, two instances of R.sup.XB are joined to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms of the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.

(221) Any one of Formulae (II), (II), and (II) includes Y.sup.B moieties. In certain embodiments, all instances of Y.sup.B are the same. In certain embodiments, at least two instances of Y.sup.B are different from each other. In certain embodiments, at least one instance of Y.sup.B is O. In certain embodiments, each instance of Y.sup.B is O. In certain embodiments, at least one instance of Y.sup.B is S. In certain embodiments, at least one instance of Y.sup.B is NR.sup.YB. In certain embodiments, at least one instance of Y.sup.B is NH. In certain embodiments, at least one instance of Y.sup.B is N(substituted or unsubstituted C.sub.1-6 alkyl, e.g., methyl).

(222) In certain embodiments, all instances of R.sup.YB are the same. In certain embodiments, at least two instances of R.sup.YB are different from each other. In certain embodiments, at least one instance of R.sup.YB is H. In certain embodiments, at least one instance of R.sup.YB is substituted or unsubstituted C.sub.1-6alkyl. In certain embodiments, at least one instance of R.sup.YB is methyl. In certain embodiments, at least one instance of R.sup.YB is ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, at least one instance of R.sup.YB is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

(223) Any one of Formulae (II), (II), and (II) includes substituents R.sup.B. In certain embodiments, at least about 10%, at least about 20%, at least about 30%, or at least about 40% of the total instances of R.sup.B are the same. In certain embodiments, at least about 50% of the total instances of R.sup.B are the same. In certain embodiments, at least about 60% of the total instances of R.sup.B are the same. In certain embodiments, at least about 70% of the total instances of R.sup.B are the same. In certain embodiments, at least about 80% of the total instances of R.sup.B are the same. In certain embodiments, at least about 90% of the total instances of R.sup.B are the same. In certain embodiments, at least about 95% of the total instances of R.sup.B are the same. In certain embodiments, all instances of R.sup.B are the same. In certain embodiments, at least two instances of R.sup.B are different from each other. In certain embodiments, at least one instance of R.sup.B is H. In certain embodiments, at least one instance of R.sup.B is of the formula:

(224) ##STR00210##
In certain embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the total instances of R.sup.B are independently of the formula:

(225) ##STR00211##
In certain embodiments, all instances of R.sup.B are independently of the formula:

(226) ##STR00212##

(227) Any one of Formulae (II), (II), and (II) includes one or more substituents R.sup.B1. In certain embodiments, all instances of R.sup.B1 are the same. In certain embodiments, all instances of R.sup.B1 that are not hydrogen are the same. In certain embodiments, at least two instances of R.sup.B1 are different from each other. In certain embodiments, at least one instance of R.sup.B1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted alkyl. In certain embodiments, each instance of R.sup.B1 is independently substituted or unsubstituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.B1 is substituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.B1 is a moiety shown in Table 2. In certain embodiments, each instance of R.sup.B1 is independently a moiety shown in Table 2. In certain embodiments, each instance of R.sup.B1 is a moiety shown in Table 2. In certain embodiments, at least one instance of R.sup.B1 is C.sub.1-30 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.B1 is C.sub.1-30 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.B1 is C.sub.1-30 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.B1 is a moiety shown in Table 1. In certain embodiments, each instance of R.sup.B1 is independently a moiety shown in Table 1. In certain embodiments, each instance of R.sup.B1 is a moiety shown in Table 1. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted and unbranched C.sub.1-30 alkyl. In certain embodiments, each instance of R.sup.B1 is independently substituted or unsubstituted C.sub.4-22 alkyl (e.g., substituted or unsubstituted C.sub.4-18 alkyl). In certain embodiments, at least one instance of R.sup.B1 is substituted C.sub.4-18 alkyl. In certain embodiments, at least one instance of R.sup.B1 is C.sub.4-18 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.B1 is C.sub.4-18 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.B1 is C.sub.4-18 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted C.sub.4-18 alkyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted and unbranched C.sub.4-18 alkyl. In certain embodiments, each instance of R.sup.B1 is independently substituted or unsubstituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.B1 is substituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.B1 is C.sub.6-14 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.B1 is C.sub.6-14 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.B1 is C.sub.6-14 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted and unbranched C.sub.6-14 alkyl. In certain embodiments, each instance of R.sup.B1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33. In certain embodiments, each instance of R.sup.B1 is n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(228) In certain embodiments, at least one instance of R.sup.B1 is substituted alkenyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted alkenyl. In certain embodiments, each instance of R.sup.B1 is independently substituted or unsubstituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is substituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is C.sub.2-30 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.B1 is C.sub.2-30 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.B1 is C.sub.2-30 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is a moiety shown in Table 3. In certain embodiments, each instance of R.sup.B1 is independently a moiety shown in Table 3. In certain embodiments, each instance of R.sup.B1 is a moiety shown in Table 3. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted and unbranched C.sub.2-30 alkenyl. In certain embodiments, each instance of R.sup.B1 is independently substituted or unsubstituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is substituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is C.sub.4-18 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.B1 is C.sub.4-18 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.B1 is C.sub.4-18 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted and unbranched C.sub.4-18 alkenyl. In certain embodiments, each instance of R.sup.B1 is independently substituted or unsubstituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is substituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is C.sub.6-14 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.B1 is C.sub.6-14 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.B1 is C.sub.6-14 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.B1 is unsubstituted and unbranched C.sub.6-14 alkenyl.

(229) In certain embodiments, each instance of b is 1. In certain embodiments, each instance of b is 2. In certain embodiments, each instance of b is 3. In certain embodiments, each instance of b is 4. In certain embodiments, each instance of b is 5.

(230) In certain embodiments, each instance of m is 0. In certain embodiments, each instance of m is 1. In certain embodiments, each instance of m is 2. In certain embodiments, each instance of m is 3. In certain embodiments, each instance of m is 4. In certain embodiments, each instance of m is 5. In certain embodiments, each instance of m is 6.

(231) In certain embodiments, each instance of v is 1. In certain embodiments, each instance of v is 2. In certain embodiments, each instance of v is 3. In certain embodiments, each instance of v is 4. In certain embodiments, each instance of v is 5. In certain embodiments, each instance of v is 6. In certain embodiments, each instance of v is 7. In certain embodiments, each instance of v is 8. In certain embodiments, each instance of v is 9. In certain embodiments, each instance of v is 10.

(232) In certain embodiments, q is an integer between 1 and 1000, inclusive. In certain embodiments, q is an integer between 1 and 300, inclusive. In certain embodiments, q is an integer between 1 and 100, inclusive. In certain embodiments, q is an integer between 1 and 70, inclusive. In certain embodiments, q is an integer between 1 and 50, inclusive. In certain embodiments, q is an integer between 1 and 30, inclusive. In certain embodiments, q is an integer between 5 and 30, inclusive. In certain embodiments, q is an integer between 10 and 20, inclusive. In certain embodiments, q is an integer between 1 and 15, inclusive. In certain embodiments, q is an integer between 5 and 15, inclusive. In certain embodiments, q is 10 or 11.

(233) In certain embodiments, the polymer of Formula (II) is of the formula:

(234) ##STR00213##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(235) In certain embodiments, the polymer of Formula (II) is of the formula:

(236) ##STR00214##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(237) In certain embodiments, the polymer of Formula (II) is of the formula:

(238) ##STR00215##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(239) In certain embodiments, the polymer of Formula (II) is of the formula:

(240) ##STR00216##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(241) In certain embodiments, the polymer of Formula (II) is of the formula:

(242) ##STR00217##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(243) In certain embodiments, the polymer of Formula (II) is of the formula:

(244) ##STR00218##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(245) In certain embodiments, the polymer of Formula (II) is of the formula:

(246) ##STR00219##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(247) In certain embodiments, the polymer of Formula (II) is of the formula:

(248) ##STR00220##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(249) In certain embodiments, the polymer of Formula (II) is of the formula:

(250) ##STR00221##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(251) In certain embodiments, the polymer of Formula (II) is of the formula:

(252) ##STR00222##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(253) In certain embodiments, the polymer of Formula (II) is of the formula:

(254) ##STR00223##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(255) In certain embodiments, the polymer of Formula (II) is of the formula:

(256) ##STR00224##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(257) In certain embodiments, the polymer of Formula (II) is of the formula:

(258) ##STR00225##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(259) In certain embodiments, the polymer of Formula (II) is of the formula:

(260) ##STR00226##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(261) In certain embodiments, the polymer of Formula (II) is of the formula:

(262) ##STR00227##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(263) In certain embodiments, the polymer of Formula (II) is of the formula:

(264) ##STR00228##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(265) In certain embodiments, the polymer of Formula (II) is of the formula:

(266) ##STR00229##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(267) In certain embodiments, the polymer of Formula (II) is of the formula:

(268) ##STR00230##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(269) In certain embodiments, the polymer of Formula (II) is of the formula:

(270) ##STR00231##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(271) In certain embodiments, the polymer of Formula (II) is of the formula:

(272) ##STR00232##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(273) In certain embodiments, the polymer of Formula (II) is of the formula:

(274) ##STR00233##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(275) In certain embodiments, the polymer of Formula (II) is of the formula:

(276) ##STR00234##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(277) In certain embodiments, the polymer of Formula (II) is of the formula:

(278) ##STR00235##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(279) In certain embodiments, the polymer of Formula (II) is of the formula:

(280) ##STR00236##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(281) In certain embodiments, the polymer of Formula (II) is of the formula:

(282) ##STR00237##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(283) In certain embodiments, the polymer of Formula (II) is of the formula:

(284) ##STR00238##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(285) In certain embodiments, the polymer of Formula (II) is of the formula:

(286) ##STR00239##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(287) In another aspect, the present disclosure provides polymers of Formula (III):

(288) ##STR00240##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(289) X.sup.C is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.XC, N(R.sup.XC).sub.2, SR.sup.XC, CN, SCN, C(NR.sup.XC)R.sup.XC, C(NR.sup.XC)OR.sup.XC, C(NR.sup.XC)N(R.sup.XC).sub.2, C(O)R.sup.XC, C(O)OR.sup.XC, or C(O)N(R.sup.XC).sub.2, NO.sub.2, NR.sup.XCC(O)R.sup.XC, NR.sup.XCC(O)OR.sup.XC, NR.sup.XCC(O)N(R.sup.XC).sub.2, OC(O)R.sup.XC, OC(O)OR.sup.XC, or OC(O)N(R.sup.XC).sub.2, wherein each instance of R.sup.XC is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XC are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

(290) each instance of Y.sup.C is independently O, S, or NR.sup.YC, wherein each instance of R.sup.YC is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(291) each instance of R.sup.C is independently hydrogen or a moiety of the formula:

(292) ##STR00241##
wherein at least one instance of R.sup.C is of the formula:

(293) ##STR00242##
each instance of Z is independently O or NR.sup.C4; each instance of R.sup.C1 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; each instance of R.sup.C2 is independently hydrogen or substituted or unsubstituted alkyl; each instance of R.sup.C3 is independently hydrogen or substituted or unsubstituted alkyl; and each instance of R.sup.C4 is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(294) each instance of c is 1, 2, 3, 4, or 5;

(295) each instance of n is 0, 1, 2, 3, 4, 5, or 6;

(296) each instance of w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

(297) r is an integer between 1 and 1000, inclusive.

(298) In another aspect, the present disclosure provides polymers of Formula (III):

(299) ##STR00243##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(300) each instance of X.sup.C is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.XC, N(R.sup.XC).sub.2, SR.sup.XC, CN, SCN, C(NR.sup.XC)R.sup.XC, C(NR.sup.XC)OR.sup.XC, C(NR.sup.XC)N(R.sup.XC).sub.2, C(O)R.sup.XC, C(O)OR.sup.XC, or C(O)N(R.sup.XC).sub.2, NO.sub.2, NR.sup.XCC(O)R.sup.XC, NR.sup.XCC(O)OR.sup.XC, NR.sup.XCC(O)N(R.sup.XC).sub.2, OC(O)R.sup.XC, OC(O)OR.sup.XC, or OC(O)N(R.sup.XC).sub.2, wherein each instance of R.sup.XC is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XC are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;

(301) each instance of Y.sup.C is independently O, S, or NR.sup.YC, wherein each instance of R.sup.YC is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(302) each instance of R.sup.C is independently hydrogen or a moiety of the formula:

(303) ##STR00244##
wherein: at least one instance of R.sup.C is of the formula:

(304) ##STR00245##
each instance of Z is independently O or NR.sup.C4; each instance of R.sup.C1 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; each instance of R.sup.C2 is independently hydrogen or substituted or unsubstituted alkyl; each instance of R.sup.C3 is independently hydrogen or substituted or unsubstituted alkyl; and each instance of R.sup.C4 is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(305) each instance of c is 1, 2, 3, 4, or 5;

(306) each instance of n is 0, 1, 2, 3, 4, 5, or 6;

(307) each instance of w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

(308) r is an integer between 1 and 1000, inclusive.

(309) In another aspect, the present disclosure provides polymers of Formula (III):

(310) ##STR00246##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(311) each instance of Y.sup.C is independently O, S, or NR.sup.YC, wherein each instance of R.sup.YC is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(312) each instance of R.sup.C is independently hydrogen or a moiety of the formula:

(313) ##STR00247##
wherein: at least one instance of R.sup.C is of the formula:

(314) ##STR00248##
each instance of Z is independently O or NR.sup.C4; each instance of R.sup.C1 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl; each instance of R.sup.C2 is independently hydrogen or substituted or unsubstituted alkyl; each instance of R.sup.C3 is independently hydrogen or substituted or unsubstituted alkyl; and each instance of R.sup.C4 is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(315) each instance of c is 1, 2, 3, 4, or 5;

(316) each instance of n is 0, 1, 2, 3, 4, 5, or 6;

(317) each instance of w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

(318) r is an integer between 1 and 1000, inclusive.

(319) Formula (III) includes end group X.sup.C. In certain embodiments, X.sup.C is substituted alkyl. In certain embodiments, X.sup.C is unsubstituted alkyl. In certain embodiments, X.sup.C is unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.C is substituted C.sub.1-6 alkyl. In certain embodiments, X.sup.C is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, X.sup.C is CH.sub.3. In certain embodiments, X.sup.C is substituted methyl. In certain embodiments, X.sup.C is CH.sub.2F. In certain embodiments, X.sup.C is CHF.sub.2. In certain embodiments, X.sup.C is CF.sub.3. In certain embodiments, X.sup.C is ethyl. In certain embodiments, X.sup.C is propyl. In certain embodiments, X.sup.C is butyl. In certain embodiments, X.sup.C is pentyl. In certain embodiments, X.sup.C is hexyl. In certain embodiments, X.sup.C is halogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.C is substituted alkenyl. In certain embodiments, X.sup.C is unsubstituted alkenyl. In certain embodiments, X.sup.C is substituted alkynyl. In certain embodiments, X.sup.C is unsubstituted alkynyl. In certain embodiments, X.sup.C is substituted carbocyclyl. In certain embodiments, X.sup.C is unsubstituted carbocyclyl. In certain embodiments, X.sup.C is saturated carbocyclyl. In certain embodiments, X.sup.C is unsaturated carbocyclyl. In certain embodiments, X.sup.C is monocyclic carbocyclyl. In certain embodiments, X.sup.C is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, X.sup.C is substituted heterocyclyl. In certain embodiments, X.sup.C is unsubstituted heterocyclyl. In certain embodiments, X.sup.C is saturated heterocyclyl. In certain embodiments, X.sup.C is unsaturated heterocyclyl. In certain embodiments, X.sup.C is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, X.sup.C is monocyclic heterocyclyl. In certain embodiments, X.sup.C is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, X.sup.C is substituted aryl. In certain embodiments, X.sup.C is unsubstituted aryl. In certain embodiments, X.sup.C is 6- to 10-membered aryl. In certain embodiments, X.sup.C is substituted phenyl. In certain embodiments, X.sup.C is unsubstituted phenyl. In certain embodiments, X.sup.C is substituted heteroaryl. In certain embodiments, X.sup.C is unsubstituted heteroaryl. In certain embodiments, X.sup.C is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, X.sup.C is monocyclic heteroaryl. In certain embodiments, X.sup.C is 5-membered, monocyclic heteroaryl. In certain embodiments, X.sup.C is 6-membered, monocyclic heteroaryl. In certain embodiments, X.sup.C is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, X.sup.C is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, X.sup.C is OR.sup.XC. In certain embodiments, X.sup.C is OH. In certain embodiments, X.sup.C is OR.sup.XC, wherein R.sup.XC is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, X.sup.C is OMe. In certain embodiments, X.sup.C is OEt, OPr, OBu, or OBn. In certain embodiments, X.sup.C is OPh. In certain embodiments, X.sup.C is SR.sup.XC. In certain embodiments, X.sup.C is SH. In certain embodiments, X.sup.C is SMe. In certain embodiments, X.sup.C is N(R.sup.XC).sub.2. In certain embodiments, X.sup.C is NH.sub.2. In certain embodiments, X.sup.C is NHMe. In certain embodiments, X.sup.C is NMe.sub.2. In certain embodiments, X.sup.C is OR.sup.XC or N(R.sup.XC).sub.2. In certain embodiments, X.sup.C is C(NR.sup.XC)R.sup.XC, C(NR.sup.XC)OR.sup.XC, or C(NR.sup.XC)N(R.sup.XC).sub.2. In certain embodiments, X.sup.C is C(O)R.sup.XC or C(O)OR.sup.XC. In certain embodiments, X.sup.C is C(O)N(R.sup.XC).sub.2. In certain embodiments, X.sup.C is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2.

(320) Formula (III) includes end groups X.sup.C. In certain embodiments, all instances of X.sup.C are the same. In certain embodiments, two instances of X.sup.C are not the same. In certain embodiments, at least one instance of X.sup.C is substituted alkyl. In certain embodiments, at least one instance of X is unsubstituted alkyl. In certain embodiments, at least one instance of X.sup.C is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.C is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of X.sup.C is CH.sub.3. In certain embodiments, at least one instance of X.sup.C is substituted methyl. In certain embodiments, at least one instance of X is CH.sub.2F. In certain embodiments, at least one instance of X.sup.C is CHF.sub.2. In certain embodiments, at least one instance of X.sup.C is CF.sub.3. In certain embodiments, at least one instance of X.sup.C is ethyl. In certain embodiments, at least one instance of X.sup.C is propyl. In certain embodiments, at least one instance of X.sup.C is butyl. In certain embodiments, at least one instance of X.sup.C is pentyl. In certain embodiments, at least one instance of X.sup.C is hexyl. In certain embodiments, at least one instance of X.sup.C is halogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.C is substituted alkenyl. In certain embodiments, at least one instance of X.sup.C is unsubstituted alkenyl. In certain embodiments, at least one instance of X.sup.C is substituted alkynyl. In certain embodiments, at least one instance of X.sup.C is unsubstituted alkynyl. In certain embodiments, at least one instance of X.sup.C is substituted carbocyclyl. In certain embodiments, at least one instance of X.sup.C is unsubstituted carbocyclyl. In certain embodiments, at least one instance of X.sup.C is saturated carbocyclyl. In certain embodiments, at least one instance of X.sup.C is unsaturated carbocyclyl. In certain embodiments, at least one instance of X.sup.C is monocyclic carbocyclyl. In certain embodiments, at least one instance of X.sup.C is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of X.sup.C is substituted heterocyclyl. In certain embodiments, at least one instance of X.sup.C is unsubstituted heterocyclyl. In certain embodiments, at least one instance of X.sup.C is saturated heterocyclyl. In certain embodiments, at least one instance of X.sup.C is unsaturated heterocyclyl. In certain embodiments, at least one instance of X.sup.C is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of X.sup.C is monocyclic heterocyclyl. In certain embodiments, at least one instance of X.sup.C is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of X.sup.C is substituted aryl. In certain embodiments, at least one instance of X.sup.C is unsubstituted aryl. In certain embodiments, at least one instance of X.sup.C is 6- to 10-membered aryl. In certain embodiments, at least one instance of X.sup.C is substituted phenyl. In certain embodiments, at least one instance of X.sup.C is unsubstituted phenyl. In certain embodiments, at least one instance of X.sup.C is substituted heteroaryl. In certain embodiments, at least one instance of X.sup.C is unsubstituted heteroaryl. In certain embodiments, at least one instance of X.sup.C is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of X.sup.C is monocyclic heteroaryl. In certain embodiments, at least one instance of X.sup.C is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of X is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of X.sup.C is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of X.sup.C is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of X.sup.C is OR.sup.XC. In certain embodiments, at least one instance of X.sup.C is OH. In certain embodiments, at least one instance of X.sup.C is OR.sup.XC, wherein R.sup.XC is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of X.sup.C is OMe. In certain embodiments, at least one instance of X is OEt, OPr, OBu, or OBn. In certain embodiments, at least one instance of X.sup.C is OPh. In certain embodiments, at least one instance of X.sup.C is SR.sup.XC. In certain embodiments, at least one instance of X.sup.C is SH. In certain embodiments, at least one instance of X.sup.C is SMe. In certain embodiments, at least one instance of X.sup.C is N(R.sup.XC).sub.2. In certain embodiments, at least one instance of X.sup.C is NH.sub.2. In certain embodiments, at least one instance of X.sup.C is NHMe. In certain embodiments, at least one instance of X.sup.C is NMe.sub.2. In certain embodiments, at least one instance of X.sup.C is OR.sup.XC or N(R.sup.XC).sub.2. In certain embodiments, at least one instance of X.sup.C is C(NR.sup.XC)R.sup.XC, C(NR.sup.XC)OR.sup.XC, or C(NR.sup.XC)N(R.sup.XC).sub.2. In certain embodiments, at least one instance of X.sup.C is C(O)R.sup.XC or C(O)OR.sup.XC. In certain embodiments, at least one instance of X.sup.C is C(O)N(R.sup.XC).sub.2. In certain embodiments, at least one instance of X.sup.C is C(O)NMe.sub.2, C(O)NHMe, or C(O)NH.sub.2.

(321) For any of the X.sup.C that include an R.sup.XC moiety described herein, any of the following embodiments for R.sup.XC may be applicable. In certain embodiments, R.sup.XC is H. In certain embodiments, R.sup.XC is substituted acyl. In certain embodiments, R.sup.XC is unsubstituted acyl. In certain embodiments, R.sup.XC is acetyl. In certain embodiments, R.sup.XC is substituted alkyl. In certain embodiments, R.sup.XC is unsubstituted alkyl. In certain embodiments, R.sup.XC is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.XC is methyl. In certain embodiments, R.sup.XC is ethyl. In certain embodiments, R.sup.XC is propyl. In certain embodiments, R.sup.XC is butyl. In certain embodiments, R.sup.XC is pentyl. In certain embodiments, R.sup.XC is hexyl. In certain embodiments, R.sup.XC is substituted alkenyl. In certain embodiments, R.sup.XC is unsubstituted alkenyl. In certain embodiments, R.sup.XC is substituted alkynyl. In certain embodiments, R.sup.XC is unsubstituted alkynyl. In certain embodiments, R.sup.XC is substituted or unsubstituted carbocyclyl. In certain embodiments, R.sup.XC is saturated carbocyclyl. In certain embodiments, R.sup.XC is unsaturated carbocyclyl. In certain embodiments, R.sup.XC is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.XC is substituted or unsubstituted heterocyclyl. In certain embodiments, R.sup.XC is saturated heterocyclyl. In certain embodiments, R.sup.XC is unsaturated heterocyclyl. In certain embodiments, R.sup.XC is heterocyclyl, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.XC is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.XC is substituted or unsubstituted aryl. In certain embodiments, R.sup.XC is 6- to 10-membered aryl. In certain embodiments, R.sup.XC is monocyclic aryl. In certain embodiments, R.sup.XC is substituted phenyl. In certain embodiments, R.sup.XC is unsubstituted phenyl. In certain embodiments, R.sup.XC is bicyclic aryl. In certain embodiments, R.sup.XC is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.XC is heteroaryl, wherein one, two, three, or four atoms of the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.XC is monocyclic heteroaryl. In certain embodiments, R.sup.XC is 5- or 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.XC is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, R.sup.XC is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, R.sup.XC is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom. In certain embodiments, R.sup.XC is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.XC is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R.sup.XC is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.XC is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two instances of R.sup.XC are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.XC are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.XC are joined to form a heterocyclic ring, wherein one, two, or three atoms of the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.XC are joined to form a 3- to 7-membered, monocyclic heterocyclic ring. In certain embodiments, two instances of R.sup.XC are joined to form a substituted or unsubstituted heteroaryl ring. In certain embodiments, two instances of R.sup.XC are joined to form a substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, three, or four atoms of the heteroaryl ring system are independently nitrogen, oxygen, or sulfur.

(322) Any one of Formulae (III), (III), and (III) includes Y.sup.C moieties. In certain embodiments, all instances of Y.sup.C are the same. In certain embodiments, at least two instances of Y.sup.C are different from each other. In certain embodiments, at least one instance of Y.sup.C is O. In certain embodiments, each instance of Y.sup.C is O. In certain embodiments, at least one instance of Y.sup.C is S. In certain embodiments, at least one instance of Y.sup.C is NR.sup.YC. In certain embodiments, at least one instance of Y.sup.C is NH. In certain embodiments, at least one instance of Y.sup.C is N(substituted or unsubstituted C.sub.1-6 alkyl, e.g., methyl).

(323) In certain embodiments, all instances of R.sup.YC are the same. In certain embodiments, at least two instances of R.sup.YC are different from each other. In certain embodiments, at least one instance of R.sup.YC is H. In certain embodiments, at least one instance of R.sup.YC is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.YC is methyl. In certain embodiments, at least one instance of R.sup.YC is ethyl, propyl, butyl, pentyl, or hexyl. In certain embodiments, at least one instance of R.sup.YC is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

(324) Any one of Formulae (III), (III), and (III) includes substituents R.sup.C. In certain embodiments, at least about 10%, at least about 20%, at least about 30%, or at least about 40% of the total instances of R.sup.C are the same. In certain embodiments, at least about 50% of the total instances of R.sup.C are the same. In certain embodiments, at least about 60% of the total instances of R.sup.C are the same. In certain embodiments, at least about 70% of the total instances of R.sup.C are the same. In certain embodiments, at least about 80% of the total instances of R.sup.C are the same. In certain embodiments, at least about 90% of the total instances of R.sup.C are the same. In certain embodiments, at least about 95% of the total instances of R.sup.C are the same. In certain embodiments, all instances of R.sup.C are the same. In certain embodiments, at least two instances of R.sup.C are different from each other. In certain embodiments, at least one instance of R.sup.C is H. In certain embodiments, at least one instance of R.sup.C is of the formula:

(325) ##STR00249##
In certain embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the total instances of R.sup.C are independently of the formula:

(326) ##STR00250##
In certain embodiments, all instances of R.sup.C are independently of the formula:

(327) ##STR00251##
In certain embodiments, at least one instance of R.sup.C is of the formula:

(328) ##STR00252##
In certain embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the total instances of R.sup.C are independently of the formula:

(329) ##STR00253##
In certain embodiments, all instances of R.sup.C are independently of the formula:

(330) ##STR00254##
In certain embodiments, at least one instance of R.sup.C is of the formula:

(331) ##STR00255##
In certain embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the total instances of R.sup.C are independently of the formula:

(332) ##STR00256##
In certain embodiments, all instances of R.sup.C are independently of the formula:

(333) ##STR00257##

(334) In certain embodiments, each instance of Z is O. In certain embodiments, each instance of Z is independently NR.sup.C4. In certain embodiments, each instance of Z is NH. In certain embodiments, each instance of Z is independently NR.sup.C4, wherein each instance of R.sup.C4 is independently substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, each instance of Z is NMe-.

(335) Any one of Formulae (III), (III), and (III) includes one or more substituents R.sup.C. In certain embodiments, all instances of R.sup.C1 are the same. In certain embodiments, all instances of R.sup.C1 that are not hydrogen are the same. In certain embodiments, at least two instances of R.sup.C1 are different from each other. In certain embodiments, at least one instance of R.sup.C1 is H. In certain embodiments, each instance of R.sup.C1 is H. In certain embodiments, at least one instance of R.sup.C1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted alkyl. In certain embodiments, each instance of R.sup.C1 is independently substituted or unsubstituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.C1 is substituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.C1 is a moiety shown in Table 2. In certain embodiments, each instance of R.sup.C1 is independently a moiety shown in Table 2. In certain embodiments, each instance of R.sup.C1 is a moiety shown in Table 2. In certain embodiments, at least one instance of R.sup.C1 is C.sub.1-30 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.C1 is C.sub.1-30 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.C1 is C.sub.1-30 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted C.sub.1-30 alkyl. In certain embodiments, at least one instance of R.sup.C1 is a moiety shown in Table 1. In certain embodiments, each instance of R.sup.C1 is independently a moiety shown in Table 1. In certain embodiments, each instance of R.sup.C1 is a moiety shown in Table 1. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted and unbranched C.sub.1-30 alkyl. In certain embodiments, each instance of R.sup.C1 is independently substituted or unsubstituted C.sub.4-22 alkyl (e.g., substituted or unsubstituted C.sub.4-18 alkyl). In certain embodiments, at least one instance of R.sup.C1 is substituted C.sub.4-18 alkyl. In certain embodiments, at least one instance of R.sup.C1 is C.sub.4-18 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.C1 is C.sub.4-18 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.C1 is C.sub.4-18 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted C.sub.4-18 alkyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted and unbranched C.sub.4-18 alkyl. In certain embodiments, each instance of R.sup.C1 is independently substituted or unsubstituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.C1 is substituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.C1 is C.sub.6-14 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.C1 is C.sub.6-14 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.C1 is C.sub.6-14 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted C.sub.6-14 alkyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted and unbranched C.sub.6-14 alkyl. In certain embodiments, each instance of R.sup.C1 is independently n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33. In certain embodiments, each instance of R.sup.C1 is n-C.sub.6H.sub.13, n-C.sub.8H.sub.17, n-C.sub.10H.sub.21, n-C.sub.12H.sub.25, n-C.sub.14H.sub.29, or n-C.sub.16H.sub.33.

(336) In certain embodiments, at least one instance of R.sup.C1 is substituted alkenyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted alkenyl. In certain embodiments, each instance of R.sup.C1 is independently substituted or unsubstituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is substituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is C.sub.2-30 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.C1 is C.sub.2-30 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.C1 is C.sub.2-30 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted C.sub.2-30 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is a moiety shown in Table 3. In certain embodiments, each instance of R.sup.C1 is independently a moiety shown in Table 3. In certain embodiments, each instance of R.sup.C1 is a moiety shown in Table 3. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted and unbranched C.sub.2-30 alkenyl. In certain embodiments, each instance of R.sup.C1 is independently substituted or unsubstituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is substituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is C.sub.4-18 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.C1 is C.sub.4-18 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.C1 is C.sub.4-18 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted C.sub.4-18 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted and unbranched C.sub.4-18 alkenyl. In certain embodiments, each instance of R.sup.C1 is independently substituted or unsubstituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is substituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is C.sub.6-14 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.C1 is C.sub.6-14 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.C1 is C.sub.6-14 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted C.sub.6-14 alkenyl. In certain embodiments, at least one instance of R.sup.C1 is unsubstituted and unbranched C.sub.6-14 alkenyl.

(337) In certain embodiments, all instances of R.sup.C2 are the same. In certain embodiments, at least two instances of R.sup.C2 are different from each other. In certain embodiments, at least one instance of R.sup.C2 is H. In certain embodiments, each instance of R.sup.C2 is H. In certain embodiments, at least one instance of R.sup.C2 is substituted alkyl. In certain embodiments, at least one instance of R.sup.C2 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.C2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, both instances of R.sup.C2 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C2 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C2 is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.C2 is CH.sub.3. In certain embodiments, at least one instance of R.sup.C2 is substituted methyl. In certain embodiments, at least one instance of R.sup.C2 is CH.sub.2F. In certain embodiments, at least one instance of R.sup.C2 is CHF.sub.2. In certain embodiments, at least one instance of R.sup.C2 is CF.sub.3. In certain embodiments, at least one instance of R.sup.C2 is ethyl. In certain embodiments, at least one instance of R.sup.C2 is propyl. In certain embodiments, at least one instance of R.sup.C2 is butyl. In certain embodiments, at least one instance of R.sup.C2 is pentyl. In certain embodiments, at least one instance of R.sup.C2 is hexyl.

(338) In certain embodiments, all instances of R.sup.C3 are the same. In certain embodiments, at least two instances of R.sup.C3 are different from each other. In certain embodiments, at least one instance of R.sup.C3 is H. In certain embodiments, each instance of R.sup.C3 is H. In certain embodiments, at least one instance of R.sup.C3 is substituted alkyl. In certain embodiments, at least one instance of R.sup.C3 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.C3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, both instances of R.sup.C3 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C3 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C3 is C.sub.1-6alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.C3 is CH.sub.3. In certain embodiments, at least one instance of R.sup.C3 is substituted methyl. In certain embodiments, at least one instance of R.sup.C3 is CH.sub.2F. In certain embodiments, at least one instance of R.sup.C3 is CHF.sub.2. In certain embodiments, at least one instance of R.sup.C3 is CF.sub.3. In certain embodiments, at least one instance of R.sup.C3 is ethyl. In certain embodiments, at least one instance of R.sup.C3 is propyl. In certain embodiments, at least one instance of R.sup.C3 is butyl. In certain embodiments, at least one instance of R.sup.C3 is pentyl. In certain embodiments, at least one instance of R.sup.C3 is hexyl.

(339) In certain embodiments, all instances of R.sup.C2 and R.sup.C3 are H.

(340) In certain embodiments, all instances of R.sup.C4 are the same. In certain embodiments, at least two instances of R.sup.C4 are different from each other. In certain embodiments, at least one instance of R.sup.C4 is H. In certain embodiments, each instance of R.sup.C4 is H. In certain embodiments, at least one instance of R.sup.C4 is substituted alkyl. In certain embodiments, at least one instance of R.sup.C4 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.C4 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, both instances of R.sup.C4 are unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C4 is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.C4 is C.sub.1-6alkyl substituted with at least one halogen. In certain embodiments, at least one instance of R.sup.C4 is CH.sub.3. In certain embodiments, at least one instance of R.sup.C4 is substituted methyl. In certain embodiments, at least one instance of R.sup.C4 is CH.sub.2F. In certain embodiments, at least one instance of R.sup.C4 is CHF.sub.2. In certain embodiments, at least one instance of R.sup.C4 is CF.sub.3. In certain embodiments, at least one instance of R.sup.C4 is ethyl. In certain embodiments, at least one instance of R.sup.C4 is propyl. In certain embodiments, at least one instance of R.sup.C4 is butyl. In certain embodiments, at least one instance of R.sup.C4 is pentyl. In certain embodiments, at least one instance of R.sup.C4 is hexyl. In certain embodiments, at least one instance of R.sup.C4 is a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.C4 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

(341) In certain embodiments, each instance of c is 1. In certain embodiments, each instance of c is 2. In certain embodiments, each instance of c is 3. In certain embodiments, each instance of c is 4. In certain embodiments, each instance of c is 5.

(342) In certain embodiments, each instance of n is 0. In certain embodiments, each instance of n is 1. In certain embodiments, each instance of n is 2. In certain embodiments, each instance of n is 3. In certain embodiments, each instance of n is 4. In certain embodiments, each instance of n is 5. In certain embodiments, each instance of n is 6.

(343) In certain embodiments, each instance of w is 1. In certain embodiments, each instance of w is 2. In certain embodiments, each instance of w is 3. In certain embodiments, each instance of w is 4. In certain embodiments, each instance of w is 5. In certain embodiments, each instance of w is 6. In certain embodiments, each instance of w is 7. In certain embodiments, each instance of w is 8. In certain embodiments, each instance of w is 9. In certain embodiments, each instance of w is 10.

(344) In certain embodiments, r is an integer between 1 and 1000, inclusive. In certain embodiments, r is an integer between 1 and 300, inclusive. In certain embodiments, r is an integer between 1 and 100, inclusive. In certain embodiments, r is an integer between 1 and 70, inclusive. In certain embodiments, r is an integer between 1 and 50, inclusive. In certain embodiments, r is an integer between 1 and 30, inclusive. In certain embodiments, r is an integer between 5 and 30, inclusive. In certain embodiments, r is an integer between 10 and 20, inclusive. In certain embodiments, r is an integer between 1 and 15, inclusive. In certain embodiments, r is an integer between 5 and 15, inclusive. In certain embodiments, r is 10 or 11.

(345) In certain embodiments, the polymer of Formula (III) is of the formula:

(346) ##STR00258##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(347) In certain embodiments, the polymer of Formula (III) is of the formula:

(348) ##STR00259##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(349) In certain embodiments, the polymer of Formula (III) is of the formula:

(350) ##STR00260##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(351) In certain embodiments, the polymer of Formula (III) is of the formula:

(352) ##STR00261##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(353) In certain embodiments, the polymer of Formula (III) is of the formula:

(354) ##STR00262##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(355) In certain embodiments, the polymer of Formula (III) is of the formula:

(356) ##STR00263##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(357) In certain embodiments, the polymer of Formula (III) is of the formula:

(358) ##STR00264##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(359) In certain embodiments, the polymer of Formula (III) is of the formula:

(360) ##STR00265##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(361) In certain embodiments, the polymer of Formula (III) is of the formula:

(362) ##STR00266##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(363) In certain embodiments, the polymer of Formula (III) is of the formula:

(364) ##STR00267##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(365) In certain embodiments, the polymer of Formula (III) is of the formula:

(366) ##STR00268##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(367) In certain embodiments, the polymer of Formula (III) is of the formula:

(368) ##STR00269##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(369) In certain embodiments, the polymer of Formula (III) is of the formula:

(370) ##STR00270##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(371) In certain embodiments, the polymer of Formula (III) is of the formula:

(372) ##STR00271##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(373) In certain embodiments, the polymer of Formula (III) is of the formula:

(374) ##STR00272##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(375) In certain embodiments, the polymer of Formula (III) is of the formula:

(376) ##STR00273##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(377) In certain embodiments, the polymer of Formula (III) is of the formula:

(378) ##STR00274##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(379) In certain embodiments, the polymer of Formula (III) is of the formula:

(380) ##STR00275##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(381) In certain embodiments, the polymer of Formula (III) is of the formula:

(382) ##STR00276##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(383) In certain embodiments, the polymer of Formula (III) is of the formula:

(384) ##STR00277##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(385) In certain embodiments, the polymer of Formula (III) is of the formula:

(386) ##STR00278##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(387) In certain embodiments, the polymer of Formula (III) is of the formula:

(388) ##STR00279##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(389) In certain embodiments, the polymer of Formula (III) is of the formula:

(390) ##STR00280##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(391) In certain embodiments, the polymer of Formula (III) is of the formula:

(392) ##STR00281##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(393) In certain embodiments, the polymer of Formula (III) is of the formula:

(394) ##STR00282##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(395) In certain embodiments, the polymer of Formula (III) is of the formula:

(396) ##STR00283##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(397) In certain embodiments, the polymer of Formula (III) is of the formula:

(398) ##STR00284##
or a salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled derivative thereof.

(399) In another aspect, the present disclosure provides polymers of Formula (IV):

(400) ##STR00285##
and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(401) each instance of T is a divalent carbohydrate moiety;

(402) X is X.sup.A, X.sup.B, or X.sup.C;

(403) each instance of R is independently R.sup.A, R.sup.B, or R.sup.C;

(404) each instance of d is a, b, or c;

(405) each instance of j is k, m, or n; and

(406) s is p, q, or r;

(407) wherein X.sup.A, X.sup.B, X.sup.C, R.sup.A, R.sup.B, R.sup.C, a, b, c, k, m, n, p, q, and r are as described herein.

(408) In certain embodiments, each instance of T is a divalent monosaccharide moiety. In certain embodiments, each instance of T is a divalent disaccharide moiety. In certain embodiments, the disaccharide is sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, or rutinose. In certain embodiments, each instance of T is a divalent polysaccharide moiety. In certain embodiments, the polysaccharide is alginate or chitosan. In certain embodiments, the polysaccharide is dextran, hyarulonan, pullulan, cyclodextrin, schizopyllan, cellulose, or lipopolysaccharide.

(409) In certain embodiments, each instance of R is independently R.sup.A. In certain embodiments, each instance of R is independently R.sup.B. In certain embodiments, each instance of R is independently R.sup.C.

(410) In certain embodiments, a polymer described herein is a polymer of Formula (I), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a polymer described herein is a polymer of Formula (I), or a salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (I) or (I), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a polymer described herein is a polymer of Formula (I) or (I), or a salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (I) or (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (II), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a polymer described herein is a polymer of Formula (II), or a salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (II) or (II), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a polymer described herein is a polymer of Formula (II) or (II), or a salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (II) or (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (III), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a polymer described herein is a polymer of Formula (III), or a salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (III), or a pharmaceutically acceptable salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (III) or (III), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a polymer described herein is a polymer of Formula (III) or (III), or a salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (III) or (III), or a pharmaceutically acceptable salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (IV), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a polymer described herein is a polymer of Formula (IV), or a salt thereof. In certain embodiments, a polymer described herein is a polymer of Formula (IV), or a pharmaceutically acceptable salt thereof.

(411) There is a growing interest in use of messenger RNA (mRNA) as a therapeutic strategy..sup.1-5 For example, preclinical and clinical studies have explored mRNA for use as vaccines through local administration of naked mRNA or mRNA-transfected dendritic cells to induce antigen-specific immune response..sup.1-3 Recently, Phua compared the delivery efficiency of different administration methods using stemfect mRNA transfection agents in mice..sup.4 Su developed lipid based nanoparticles for intranasal delivery of mRNA to induce luciferase expression in mice..sup.6 Through intratracheal delivery of mRNA for surfactant protein B (SP-B), Kormann reported therapeutic activity in a mouse model of lethal congenital lung disease caused by SP-B deficiency..sup.7 Zangi has reported local administration of modified mRNA in mice for the treatment of myocardial infarction..sup.7, 8 The potential utility of mRNA as a method to promote protein secretion was reported by Kariko, who demonstrated delivery of erythropoietin (EPO) mRNA via intraperitoneal administration in mice and macaques..sup.9

(412) Compared with targeting through local administration, systemic administration has the potential to access more organs and cell types through the bloodstream..sup.10 However, several physiologic barriers impede access of mRNA formulations following systemic administration..sup.1-3 In general, after intravenous administration, mRNA formulations must traverse the vascular endothelial barrier and then pass through extracellular matrix to access the tissue of interest..sup.10 Additionally, intravascular therapies must avoid filtration by the kidneys and uptake by immune cells. After cell internalization, the mRNA must survive and escape the endocytic pathway in order to access translational machinery in the cytosol. The efficient and safe delivery of mRNA remains a key challenge to the broad clinical application of mRNA therapeutics..sup.1

(413) The polymers described herein may be useful in delivering an agent, such as a polynucleotide (e.g., DNA (e.g., plasmid DNA) or RNA (e.g., siRNA, mRNA), or a combination thereof), to a subject, tissue, or cell. The polymers include amino groups, which may increase electrostatic complexation and entrapment of negatively-charged agents (e.g., polynucleotide, e.g., mRNA). In addition, the polymers may include multiple hydroxyl groups, which may increase hydrophilicity, while alkyl tails (brushes) included in the polymers may enable incorporation of the polymers into nanoparticle formulations (e.g., lipid-based nanoparticle formulations). This modular design offers the ability to tune the agent-delivery system through modification of a number of chemical and structural properties. The polymers described herein may also be useful in treating and/or preventing a disease (e.g., a genetic disease, proliferative disease, hematological disease, neurological disease, gastrointestinal disease, spleen disease, respiratory disease, painful condition, psychiatric disorder, musculoskeletal disease, genitourinary disease, or metabolic disorder) in a subject in need thereof. In certain embodiments, the polymers described herein are useful in gene therapy. The polymers described herein may also be useful for other applications, e.g., as an emulsion, emulsifier, or coating, each of which may be useful as a food component, for extinguishing fires, for disinfecting surfaces, or for oil cleanup; and/or as a bulk material.

(414) Methods of Preparing the Polymers and Polymers Prepared by the Methods

(415) Polymers described herein may be prepared using epoxide-amine addition reactions (e.g., Methods A, A, and A), reductive amination reactions (e.g., Methods B-1, B-1, B-1, and B-2), and Michael addition reactions (e.g., Methods C, C, and C). In another aspect, the present disclosure provides methods of preparing the polymers of Formula (I), and salts thereof (Method A), the methods including reacting a polymer of Formula (A1), or a salt thereof, with an epoxide of Formula (A2) to provide the polymer of Formula (I), or a salt thereof:

(416) ##STR00286##

(417) In another aspect, the present disclosure provides methods of preparing the polymers of Formula (I), and salts thereof (Method A), the methods including reacting a polymer of Formula (A3), or a salt thereof, with an epoxide of Formula (A2) to provide the polymer of Formula (I), or a salt thereof:

(418) ##STR00287##

(419) In another aspect, the present disclosure provides methods of preparing the polymers of Formula (I), and salts thereof (Method A), the methods including reacting a polymer of Formula (A4), or a salt thereof, with an epoxide of Formula (A2) to provide the polymer of Formula (I), or a salt thereof:

(420) ##STR00288##

(421) Another aspect of the present disclosure relates to methods of preparing the polymers of Formula (II), and salts thereof (Method B-1), the methods including reacting a polymer of Formula (B1), or a salt thereof, with an aldehyde of Formula (B2) in the presence of a reductant to provide the polymer of Formula (II), or a salt thereof:

(422) ##STR00289##

(423) Another aspect of the present disclosure relates to methods of preparing the polymers of Formula (II), and salts thereof (Method B-1), the methods including reacting a polymer of Formula (B4), or a salt thereof, with an aldehyde of Formula (B2) in the presence of a reductant to provide the polymer of Formula (II), or a salt thereof:

(424) ##STR00290##

(425) Another aspect of the present disclosure relates to methods of preparing the polymers of Formula (II), and salts thereof (Method B-1), the methods including reacting a polymer of Formula (B5), or a salt thereof, with an aldehyde of Formula (B2) in the presence of a reductant to provide the polymer of Formula (II), or a salt thereof:

(426) ##STR00291##

(427) Another aspect of the present disclosure relates to methods of preparing the polymers of Formula (II), and salts thereof (Method B-2), the methods including reducing a polymer of Formula (B3), or a salt thereof, with a reductant to provide the polymer of Formula (II), or a salt thereof:

(428) ##STR00292##
wherein each instance of Y is independently NH or a moiety of the formula:

(429) ##STR00293##
wherein at least one instance of Y is a moiety of the formula:

(430) ##STR00294##
In certain embodiments, at least about 10%, at least about 20%, at least about 30%, or at least about 40% of the total instances of Y are the same. In certain embodiments, at least about 50% of the total instances of Y are the same. In certain embodiments, at least about 60% of the total instances of Y are the same. In certain embodiments, at least about 70% of the total instances of Y are the same. In certain embodiments, at least about 80% of the total instances of Y are the same. In certain embodiments, at least about 90% of the total instances of Y are the same. In certain embodiments, at least about 95% of the total instances of Y are the same. In certain embodiments, all instances of Y are the same. In certain embodiments, at least two instances of Y are different from each other. In certain embodiments, at least one instance of Y is NH. In certain embodiments, at least one instance of Y is of the formula:

(431) ##STR00295##
In certain embodiments, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% of the total instances of Y are independently of the formula:

(432) ##STR00296##
In certain embodiments, all instances of Y are independently of the formula:

(433) ##STR00297##

(434) In certain embodiments, Method B-2 further includes reacting a polymer of Formula (B1), or a salt thereof, with an aldehyde of Formula (B2) to provide the polymer of Formula (B3), or a salt thereof. Polymers of Formulae (II) and (II) can also be prepared using a method similar to Method B-2.

(435) The reductant employed in Method B-1, B-1, B-1, or B-2 may be any reductant known in the art. In certain embodiments, the reductant is a borohydride (e.g., sodium borohydride, potassium borohydride, calcium borohydride, magnesium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride, tetrabutylammonium borohydride, methyltrioctylammonium borohydride, cetyltrimethylammonium borohydride, bis(triphenylphosphine)copper(I) borohydride, potassium tri(1-pyrazolyl)borohydride, potassium tri(3,5-dimethyl-1-pyrazolyl)borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or polymer-supported borohydride). In certain embodiments, the reductant is a borane (e.g., a borane tetrahydrofuran complex, borane dimethyl sulfide complex, borane dimethylamine complex, borane pyridine complex, borane trimethylamine complex, borane triethylamine complex, borane morpholine complex, borane tert-butylamine complex, borane-ammonia complex, borane triphenylphosphine complex, borane N,N-diethylaniline complex, borane di(tert-butyl)phosphine complex, borane diphenylphosphine complex, borane 4-methylmorpholine complex, borane N,N-diisopropylethylamine complex, borane isoamylsulfide complex, borane ethylenediamine complex, acetylthiomethyl-diphenylphosphine borane complex, 2-methylpyridine borane complex, tert-butyldimethylphosphine borane, 5-ethyl-2-methylpyridine borane complex, lithium ammonia borane, (11bR)-4,5-dihydro-3H-dinaphtho[2,1-c:1,2-e]phosphepine borane, (methoxycarbonyl)borane trimethylamine complex, dibromoborane dimethyl sulfide complex, mono-bromoborane methyl sulfide complex, dichloroborane methyl sulfide complex, 1,3-dimethylimidazol-2-ylidene borane). In certain embodiments, the reductant is a silane. In certain embodiments, the silane is of the formula: HSi(R.sup.1).sub.3, wherein each instance of R.sup.1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or OR.sup.1a, wherein each instance of R.sup.1a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an oxygen protecting group). In certain embodiments, the silane is a monoalkylsilane (e.g., BuSiH.sub.3), dialkylsilane (e.g., Et.sub.2SiH.sub.2), or trialkylsilane (e.g., Me.sub.3SiH or Et.sub.3SiH). In certain embodiments, the silane is a poly(alkylhydrosiloxane) (e.g., poly(methylhydrosiloxane) (PMHS)). In certain embodiments, the reductant is an alcohol. In certain embodiments, the alcohol is of the formula: (R.sup.2).sub.2CHOH, wherein each instance of R.sup.2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, the alcohol is methanol, ethanol, propanol (e.g., n-propanol or isopropanol), or butanol (e.g., t-butanol). In certain embodiments, the reductant is H.sub.2. In certain embodiments, the reductant is commercially available.

(436) Another aspect of the present disclosure relates to methods of preparing the polymers of Formula (III), and salts thereof (Method C), the methods including reacting a polymer of Formula (C1), or a salt thereof, with a compound of Formula (C2) to provide the polymer of Formula (III), or a salt thereof:

(437) ##STR00298##

(438) Another aspect of the present disclosure relates to methods of preparing the polymers of Formula (III), and salts thereof (Method C), the methods including reacting a polymer of Formula (C3), or a salt thereof, with a compound of Formula (C2) to provide the polymer of Formula (III), or a salt thereof:

(439) ##STR00299##

(440) Another aspect of the present disclosure relates to methods of preparing the polymers of Formula (III), and salts thereof (Method C), the methods including reacting a polymer of Formula (C4), or a salt thereof, with a compound of Formula (C2) to provide the polymer of Formula (III), or a salt thereof:

(441) ##STR00300##

(442) Another aspect of the present disclosure relates to methods of preparing the polymers of Formula (IV), and salts thereof. In certain embodiments, when X is X.sup.A, each instance of R is independently R.sup.A, each instance of d is a, each instance of j is k, and s is p, a method of preparing a polymer of Formula (IV), or a salt thereof (Method D-A), includes reacting a polymer of Formula (A), or a salt thereof, with an epoxide of Formula (A2):

(443) ##STR00301##

(444) In certain embodiments, when X is X.sup.B, each instance of R is independently R.sup.B, each instance of d is b, each instance of j is m, and s is q, a method of preparing a polymer of Formula (IV), or a salt thereof (Method D-B-1), includes reacting a polymer of Formula (A), or a salt thereof, with an aldehyde of Formula (B2) in the presence of a reductant.

(445) In certain embodiments, when X is X.sup.B, each instance of R is independently R.sup.B, each instance of d is b, each instance of j is m, and s is q, a method of preparing a polymer of Formula (IV), or a salt thereof (Method D-B-2), includes reducing a polymer of Formula (B), or a salt thereof, with a reductant:

(446) ##STR00302##
wherein each instance of Y is as described herein.

(447) In certain embodiments, when X is X.sup.C, each instance of R is independently R.sup.C, each instance of d is c, each instance of j is n, and s is r, a method of preparing a polymer of Formula (IV), or a salt thereof (Method D-C), includes reacting a polymer of Formula (A), or a salt thereof, with a compound of Formula (C2).

(448) The step(s) of the methods of preparing the polymers described herein may be performed under any suitable conditions. A suitable condition is a combination of physical and chemical parameters under which an intended product (e.g., a polymer described herein) or intermediate may be formed using the methods.

(449) A suitable condition may include the absence of a solvent (i.e., neat). A suitable condition may include a suitable solvent. In certain embodiments, the suitable solvent is an organic solvent. In certain embodiments, the suitable solvent is an aprotic organic solvent (e.g., acetonitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyl-tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether, methyl t-butyl ether (MTBE), dimethoxyethane (DME), diglyme, acetone, butanone, dichloromethane, chloroform, carbon tetrachloride, or 1,2-dichloroethane). In certain embodiments, the suitable solvent is a protic organic solvent (e.g., an alcohol, such as methanol, ethanol, propanol, or butanol). In certain embodiments, the suitable solvent is an inorganic solvent (e.g., water). In certain embodiments, the suitable solvent is a mixture of two or more solvents. In certain embodiments, the suitable solvent is commercially available.

(450) A suitable condition may also include a suitable temperature under which a step of a method of preparing a polymer described herein is performed. In certain embodiments, the suitable temperature is at least about 0 C., at least about 23 C., at least about 40 C., at least about 60 C., at least about 80 C., or at least about 100 C. In certain embodiments, the suitable temperature is not more than about 100 C., not more than about 80 C., not more than about 60 C., not more than about 40 C., not more than about 23 C., or not more than about 0 C. Combinations of the above-referenced ranges (e.g., at least about 23 C. and not more than about 60 C.) are also within the scope of the disclosure. A suitable temperature may be a variable temperature (e.g., from 23 C. to about 60 C.) during a step of a method of preparing a polymer described herein.

(451) A suitable condition may also include a suitable pressure under which a step of a method of preparing a polymer described herein is performed. In certain embodiments, the suitable pressure is about 1 atmosphere. In certain embodiments, the suitable pressure is at least about 2 atmosphere, at least about 5 atmosphere, at least about 10 atmosphere, at least about 30 atmosphere, or at least about 100 atmosphere.

(452) A suitable condition may also include a suitable atmosphere under which a step of a method of preparing a polymer described herein is performed. In certain embodiments, the suitable atmosphere is air. In certain embodiments, the suitable atmosphere is an inert atmosphere. In certain embodiments, the suitable atmosphere is a nitrogen or argon atmosphere.

(453) A suitable condition may also include a suitable time duration that a step of a method of preparing a polymer described herein lasts. In certain embodiments, the suitable time duration is in the order of minutes (e.g., about 10 minutes or about 30 minutes), hours (e.g., about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, or about 12 hours), or days (e.g., about 1 day or 2 days).

(454) A suitable condition may also include a suitable molar ratio between the reactants and/or reagents employed in a method of preparing the polymers described herein. In certain embodiments, a suitable molar ratio of (1) the nucleophilic amino groups of a polymer of Formula (A1), (A3), or (A4), to (2) an epoxide of Formula (A2) is about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:5, or about 1:10. In certain embodiments, a suitable molar ratio of (1) the nucleophilic amino groups of a polymer of Formula (B1), (B4), (B5), to (2) an aldehyde of Formula (B2) is about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:5, or about 1:10. In certain embodiments, a suitable molar ratio of (1) the nucleophilic amino groups of a polymer of Formula (C1), (C3), or (C4), to (2) a compound of Formula (C2) is about 1:1, about 1:1.2, about 1:1.5, about 1:2, about 1:5, or about 1:10.

(455) One or more intermediates resulting from a step of a method of preparing the polymers described herein may be isolated and/or purified, and the isolated and/or purified intermediates may be reacted in a next step of the method. The isolated and/or purified intermediates may be substantially free of impurities or may contain one or more other components, such as reagents and solvents employed in the step yielding the intermediates, and byproducts. The intermediates may also be reacted in a next step without being isolated and/or purified. The intermediates and/or intended products of a method of preparing a polymer described herein may be isolated and/or purified using methods known in the art, such as distillation, chromatography (e.g., normal phase chromatography (e.g., silica gel flash chromatography), reverse phase chromatography (e.g., high performance liquid chromatography (HPLC)), precipitation, decanting, filtration, centrifuge, trituration, crystallization, recrystallization, liquid-liquid phase separation, evaporation, and drying.

(456) Another aspect of the present disclosure relates to polymers prepared by a method described herein. In certain embodiments, described herein are polymers prepared by Method A, A, or A, wherein the polymer of Formula (A1), (A3), or (A4) is a poly(glycoamidoamine) in Table 4, or a salt thereof, and the epoxide of Formula (A2) is an epoxide in Table 5 or 6. In certain embodiments, the epoxide of Formula (A2) is not of the formula:

(457) ##STR00303##

(458) TABLE-US-00004 TABLE 4 Exemplary poly(glycoamidoamines) that are useful in Method A, A, A, B-1, B-1, B-1, B-2, C, C 04 (A1a) 05 (A1b) 06 (A1c) 07 (A1d) 08 (A1e) 09 (A1f) 0 (A1g) (A1h) (A1i) (A1j) (A1k) (A1o) (A1p) (A1q) (A1r) (A1s) 0 (A1t) (A1u)

(459) TABLE-US-00005 TABLE 5 Exemplary epoxides that are useful in Methods A, A, and A. 0 (A2a) (A2b) (A2c) (A2d) (A2e) (A2f) 0

(460) TABLE-US-00006 TABLE 6 Exemplary epoxides that are useful in Methods A, A, and A. 0 0

(461) In certain embodiments, a polymer described herein is a polymer prepared according to Method A, A, or A using the poly(glycoamidoamines) and epoxides in Table 7.

(462) TABLE-US-00007 TABLE 7 Exemplary polymers prepared according to Method A, A, or A using poly(glycoamidoamines) and epoxides. Poly (glyco- Polymer amidoamine) Epoxide TarN1C8 A1a A2b TarN1C10 A1a A2c TarN1C12 A1a A2d TarN1C14 A1a A2e TarN2C8 A1b A2b TarN2C10 A1b A2c TarN2C12 A1b A2d TarN2C14 A1b A2e TarN3C8 A1c A2b TarN3C10 A1c A2c TarN3C12 A1c A2d TarN3C14 A1c A2e TarN4C8 A1d A2b TarN4C10 A1d A2c TarN4C12 A1d A2d TarN4C14 A1d A2e GalN2C8 A1e A2b GalN2C10 A1e A2c GalN2C12 A1e A2d GalN2C14 A1e A2e GalN3C8 A1f A2b GalN3C10 A1f A2c GalN3C12 A1f A2d GalN3C14 A1f A2e GalN4C8 A1g A2b GalN4C10 A1g A2c GalN4C12 A1g A2d GalN4C14 A1g A2e GluN1C10 A1h A2c GluN1C12 A1h A2d GluN1C14 A1h A2e GluN2C8 A1i A2b GluN2C10 A1i A2c GluN2C12 A1i A2d GluN2C14 A1i A2e GluN3C6 A1j A2a GluN3C8 A1j A2b GluN3C10 A1j A2c GluN3C12 A1j A2d GluN3C14 A1j A2e GluN4C8 A1k A2b GluN4C10 A1k A2c GluN4C12 A1k A2d GluN4C14 A1k A2e TarN1C16 A1o A2f TarN2C16 A1b A2f TarN3C16 A1c A2f GalN2C10 A1q A2c GalN3C10 A1r A2c GalN2C12 A1q A2d GalN3C12 A1r A2d GalN2C14 A1q A2e GalN3C14 A1r A2e GalN2C16 A1q A2f GalN3C16 A1r A2f GluN2C10 A1t A2c GluN3C10 A1u A2c GluN1C12 A1s A2d GluN2C12 A1t A2d GluN3C12 A1u A2d GluN1C14 A1s A2e GluN2C14 A1t A2e GluN3C14 A1u A2e GluN1C16 A1s A2f GluN2C16 A1t A2f GluN3C16 A1u A2f

(463) In certain embodiments, described herein are polymers prepared by Method B-1, B-1, B-1, or B-2, wherein the polymer of Formula (B1) is a poly(glycoamidoamine) in Table 4, or a salt thereof, and the aldehyde of Formula (B2) is an aldehyde in Table 8 or 9.

(464) TABLE-US-00008 TABLE 8 Exemplary aldehydes that are useful in Methods B-1, B-1, B-1, and B-2. 0 0

(465) TABLE-US-00009 TABLE 9 Exemplary aldehydes that are useful in Methods B-1, B-1, B-1, and B-2. 0 00 01

(466) In certain embodiments, described herein are polymers prepared by Method C, C, or C, wherein the polymer of Formula (C1) is a poly(glycoamidoamine) in Table 4, or a salt thereof, and the compound of Formula (C2) is an acrylate in Table 10 or an acrylamide in Table 11.

(467) TABLE-US-00010 TABLE 10 Exemplary acrylates that are useful in Method C, C, or C. 02 03 04 05 06 07 08 09 0 0

(468) TABLE-US-00011 TABLE 11 Exemplary acrylamides that are useful in Method C, C, or C. 0 0

(469) In certain embodiments, described herein are polymers prepared by Method D-A. In certain embodiments, described herein are polymers prepared by Method D-B-1 or D-B-2. In certain embodiments, described herein are polymers prepared by Method D-C.

(470) A polymer of any one of Formulae (A1), (A3), (A4), (B1), (B3), (B4), (B5), (C1), (C3), and (C4) can be prepared using methods known in the art, e.g., methods disclosed in Liu et al., J. Am. Chem. Soc., 2004, 126, (24), 7422-3; Liu et al., J. Am. Chem. Soc., 2005, 127, 3004-3015; and McLendon et al., Molecular Pharmaceutics, 2010, 7, 738-750. In certain embodiments, the polydispersity index (PDI, determined by dynamic light scattering) of a polymer of any one of Formulae (A1), (A3), (A4), (B1), (B3), (B4), (B5), (C1), (C3), and (C4) is between 1.02 and 10, between 1.02 and 5, between 1.02 and 3, between 1.1 and 5, between 1.1 and 3, or between 1.2 and 2.

(471) In certain embodiments, a polymer prepared using a method described herein is a fully-substituted poly(glycoamidoamine) (e.g., no instance of R.sup.A is H, no instance of R.sup.B is H, or no instance of R.sup.C is H). In other embodiments, a polymer prepared using a method described herein is a partially substituted poly(glycoamidoamine) (e.g., at least one instance of R.sup.A is H, at least one instances of R.sup.B is H, or at least one instances of R.sup.C is H). In certain embodiments, provided are mixtures of polymers prepared by a method described herein. In certain embodiments, a provided mixture of polymers is a mixture of partially substituted poly(glycoamidoamines) described herein. In certain embodiments, a provided mixture of polymers is a mixture of partially substituted poly(glycoamidoamines) described herein and fully-substituted poly(glycoamidoamines) described herein. In certain embodiments, the polydispersity index (PDI, determined by dynamic light scattering) of a polymer prepared using a method described herein is between 1.02 and 10, between 1.02 and 5, between 1.02 and 3, between 1.1 and 5, between 1.1 and 3, or between 1.2 and 2.

(472) Compositions

(473) In another aspect, the present disclosure provides compositions comprising a polymer described herein and optionally an excipient. In certain embodiments, a composition described herein comprises a polymer described herein and an excipient. In certain embodiments, a composition described herein is a pharmaceutical composition. In certain embodiments, a composition described herein comprises a polymer described herein and a pharmaceutically acceptable excipient. In certain embodiments, a composition described herein is a composition for non-medical applications. In certain embodiments, a composition described herein is a cosmetic composition. In certain embodiments, a composition described herein comprises a polymer described herein and a cosmetically acceptable excipient. In certain embodiments, a composition described herein is a dietary composition. In certain embodiments, a composition described herein comprises a polymer described herein and a dietarily acceptable excipient. In certain embodiments, a composition described herein is a nutraceutical composition. In certain embodiments, a composition described herein comprises a polymer described herein and a nutraceutically acceptable excipient.

(474) A composition described herein may further comprise an agent (e.g., a pharmaceutical agent or diagnostic agent). In a composition described herein, an agent may form a complex with a polymer described herein. In certain embodiments, a composition described herein is useful in the delivery of the agent to a subject, tissue, or cell. In certain embodiments, a composition described herein is useful in the delivery of an effective amount of the agent to the subject, tissue, or cell.

(475) Compositions of the disclosure may improve or increase the delivery of an agent described herein to a subject, tissue, or cell. In certain embodiments, the compositions increase the delivery of the agent to a target tissue or target cell. In certain embodiments, the target tissue is liver, spleen, and/or lung. In certain embodiments, the target cell is a liver cell, spleen cell, and/or lung cell. In certain embodiments, the compositions selectively deliver the agent to the target tissue or target cell (e.g., the compositions deliver the agent to the target tissue in a greater quantity in unit time than to a non-target tissue or deliver the agent to the target cell in a greater quantity in unit time than to a non-target cell).

(476) The delivery of an agent described herein may be characterized in various ways, such as the exposure, concentration, and bioavailability of the agent. The exposure of an agent in a subject, tissue, or cell may be defined as the area under the curve (AUC) of the concentration of the agent in the subject, tissue, or cell after administering or dosing the agent. In general, an increase in exposure may be calculated by first taking the difference in: (1) a first AUC, which is the AUC measured in a subject, tissue, or cell administered or dosed with a composition described herein; and (2) a second AUC, which is the AUC measured in a subject, tissue, or cell administered or dosed with a control composition; and then by dividing the difference by the second AUC. Exposure of an agent may be measured in an appropriate animal model. The concentration of an agent and, when appropriate, its metabolite(s), in a subject, tissue, or cell is measured as a function of time after administering or dosing the agent.

(477) Concentration of an agent, and, when appropriate, of its metabolite(s), in a subject, tissue, or cell, may be measured as a function of time in vivo using an appropriate animal model. In certain embodiments, the concentration of the agent is the concentration of the agent in a target tissue or target cell. One exemplary method of determining the concentration of an agent involves dissecting of a tissue. The concentration of the agent may be determined by HPLC or LC/MS analysis.

(478) In some embodiments, a composition of the disclosure increases the delivery of an agent described herein to a subject, tissue, or cell by due to the presence of a polymer described herein. In some embodiments, the composition increases the delivery of the agent due to the presence of a complex formed between the polymer and the agent. In some embodiments, the presence of a polymer described herein increase the delivery of the agent by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 100%, at least about 2-fold, at least about 3-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, or at least about 1000-fold. In certain embodiments, a polymer described herein is present in the composition in an amount sufficient to increase the delivery of the agent by an amount described herein when administered in the composition compared to the delivery of the agent when administered in the absence of the polymer.

(479) Compositions described herein may deliver an agent selectively to a tissue or cell. In certain embodiments, the tissue or cell to which the agent is selectively delivered is a target tissue or target cell, respectively. In certain embodiments, the compositions deliver at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 70%, at least about 100%, at least about 3-fold, at least about 10-fold, at least about 30-fold, at least about 100-fold, at least about 300-fold, or at least about 1000-fold more amount of the agent in unit time to a target tissue than to a non-target tissue or to a target cell than to a non-target cell. The amount of agent may be measured by the exposure, concentration, and/or bioavailability of the agent in a tissue or cell as described herein.

(480) The compositions described herein (e.g., pharmaceutical compositions) including one or more agents (e.g., pharmaceutical agents) may be useful in treating and/or preventing a disease. In certain embodiments, the compositions are useful in gene therapy. In certain embodiments, the compositions are useful for treating and/or preventing a genetic disease. In certain embodiments, the compositions are useful for treating and/or preventing a proliferative disease. In certain embodiments, the compositions are useful for treating and/or preventing cancer. In certain embodiments, the compositions are useful for treating and/or preventing a benign neoplasm. In certain embodiments, the compositions are useful for treating and/or preventing pathological angiogenesis. In certain embodiments, the compositions are useful for treating and/or preventing an inflammatory disease. In certain embodiments, the compositions are useful for treating and/or preventing an autoimmune disease. In certain embodiments, the compositions are useful for treating and/or preventing a hematological disease. In certain embodiments, the compositions are useful for treating and/or preventing a neurological disease. In certain embodiments, the compositions are useful for treating and/or preventing a gastrointestinal disease. In certain embodiments, the compositions are useful for treating and/or preventing a liver disease. In certain embodiments, the compositions are useful for treating and/or preventing a spleen disease. In certain embodiments, the compositions are useful for treating and/or preventing a respiratory disease. In certain embodiments, the compositions are useful for treating and/or preventing a lung disease. In certain embodiments, the compositions are useful for treating and/or preventing a painful condition. In certain embodiments, the compositions are useful for treating and/or preventing a psychiatric disorder. In certain embodiments, the compositions are useful for treating and/or preventing a musculoskeletal disease. In certain embodiments, the compositions are useful for treating and/or preventing a genitourinary diseases. In certain embodiments, the compositions are useful for treating and/or preventing a metabolic disorder.

(481) The agents may be provided in an effective amount in a composition described herein. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a disease described herein. In certain embodiments, the effective amount is an amount effective for preventing a disease described herein.

(482) An effective amount of an agent may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 to about 1000 mg/kg, from about 0.01 to about 750 mg/kg, from about 0.1 to about 500 mg/kg, from about 1.0 to about 250 mg/kg, and from about 10.0 to about 150 mg/kg.

(483) A composition of the disclosure may include a particle described herein. In certain embodiments, the composition is in the form of a particle. In certain embodiments, the particle is a nanoparticle or microparticle. In certain embodiments, a composition described herein is in the form of liposomes or micelles. It is understood that, in certain embodiments, the particles, micelles, or liposomes result from self-assembly of the components of the composition. In certain embodiments, the particle, micelle, or liposome encapsulates an agent. The agent to be delivered by the particle, micelle, or liposome may be in the form of a gas, liquid, or solid. The polymers described herein may be combined with polymers (synthetic or natural), surfactants, cholesterol, carbohydrates, proteins, lipids, lipidoids, etc. to form the particles. These particles may be further combined with an excipient to form the composition. The particles, micelles, and liposomes are described in more detail herein.

(484) The compositions described herein (e.g., pharmaceutical compositions) can be prepared by any method known in the art (e.g., pharmacology). In certain embodiments, such preparatory methods include the steps of bringing a polymer described herein into association with an agent described herein (i.e., the active ingredient), optionally with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

(485) Compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A unit dose is a discrete amount of the composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

(486) Relative amounts of the active ingredient, the excipient (e.g., the pharmaceutically or cosmetically acceptable excipient), and/or any additional ingredients in a composition described herein will vary, depending upon the identity, size, and/or condition of the subject to whom the composition is administered and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

(487) Excipients used in the manufacture of provided compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

(488) Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

(489) Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

(490) Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and mixtures thereof.

(491) Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and mixtures thereof.

(492) Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

(493) Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, and mixtures thereof.

(494) Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, and dipotassium edetateke), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, tartaric acid and salts and hydrates thereof, and mixtures thereof.

(495) Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, thimerosal, and mixtures thereof.

(496) Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, sorbic acid, and mixtures thereof.

(497) Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, phenylethyl alcohol, and mixtures thereof.

(498) Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, phytic acid, and mixtures thereof.

(499) Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, Euxyl, and mixtures thereof.

(500) Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

(501) Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

(502) Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

(503) Additionally, the composition may further comprise an apolipoprotein. Previous studies have reported that Apolipoprotein E (ApoE) was able to enhance cell uptake and gene silencing for a certain type of materials. See, e.g., Akinc, A., et al., Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol Ther. 18(7): p. 1357-64. In certain embodiments, the apolipoprotein is ApoA, ApoB, ApoC, ApoE, or ApoH, or an isoform thereof.

(504) Liquid dosage forms for oral and parenteral administration include emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In certain embodiments, the emulsions, microemulsions, solutions, suspensions, syrups and elixirs are or cosmetically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

(505) Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

(506) The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

(507) In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

(508) Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

(509) Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, excipient or carrier (e.g., pharmaceutically or cosmetically acceptable excipient or carrier) such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

(510) Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

(511) The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the formulation art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

(512) Dosage forms for topical and/or transdermal administration of a composition of this disclosure may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

(513) Suitable devices for use in delivering intradermal compositions described herein include short needle devices such as those described in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Pat. Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particle delivery devices which use compressed gas to accelerate the agent in powder form through the outer layers of the skin to the dermis are suitable.

(514) Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

(515) A composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

(516) Low boiling propellants generally include liquid propellants having a boiling point of below 65 F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

(517) Compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

(518) Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

(519) Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

(520) A composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

(521) Although the descriptions of compositions provided herein are principally directed to compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

(522) Polymers described herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder, the activity of the specific active ingredient employed, the specific composition employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, route of administration, and rate of excretion of the specific active ingredient employed, the duration of the treatment, drugs used in combination or coincidental with the specific active ingredient employed, and like factors well known in the medical arts.

(523) The compositions described herein can be administered by any suitable route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. In certain embodiments, the compositions are administered by oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

(524) The exact amount of an agent required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular agent, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

(525) In certain embodiments, an effective amount of an agent for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of an agent per unit dosage form.

(526) In certain embodiments, the agents described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect.

(527) It will be appreciated that dose ranges as described herein provide guidance for the administration of provided compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

(528) Compositions described herein may further include a hydrophilic polymer (e.g., polyethylene glycol (PEG)). The compositions described herein may further include a lipid (e.g., a steroid, a substituted or unsubstituted cholesterol, or a polyethylene glycol (PEG)-containing material). In certain embodiments, the lipid included in the compositions is a triglyceride, a driglyceride, a PEGylated lipid, a phospholipid (e.g., 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)), a steroid, a substituted or unsubstituted cholesterol, an apolipoprotein, or a combination thereof. In certain embodiments, the compositions include two components selected from the group consisting of the following components: a hydrophilic polymer, a triglyceride, a driglyceride, a PEGylated lipid, a phospholipid, a steroid, a substituted or unsubstituted cholesterol, and an apolipoprotein. In certain embodiments, the compositions include three components selected from the group consisting of the following components: a hydrophilic polymer, a triglyceride, a driglyceride, a PEGylated lipid, a phospholipid, a steroid, a substituted or unsubstituted cholesterol, and an apolipoprotein. In certain embodiments, the compositions include at least four components selected from the group consisting of the following components: a hydrophilic polymer, a triglyceride, a driglyceride, a PEGylated lipid, a phospholipid, a steroid, a substituted or unsubstituted cholesterol, and an apolipoprotein. In certain embodiments, the compositions include a hydrophilic polymer, a phospholipid, a steroid, and a substituted or unsubstituted cholesterol. In certain embodiments, the compositions include PEG, DSPC, and substituted or unsubstituted cholesterol.

(529) Compositions described herein may be useful in other applications, e.g., non-medical applications. Nutraceutical compositions described herein may be useful in the delivery of an effective amount of a nutraceutical, e.g., a dietary supplement, to a subject in need thereof. Cosmetic compositions described herein may be formulated as a cream, ointment, balm, paste, film, or liquid, etc., and may be useful in the application of make-up, hair products, and materials useful for personal hygiene, etc. Compositions described herein may be useful for other non-medical applications, e.g., such as an emulsion, emulsifier, or coating, useful, for example, as a food component, for extinguishing fires, for disinfecting surfaces, for oil cleanup, and/or as a bulk material.

(530) Agents

(531) Agents that are delivered by the compositions described herein (e.g., pharmaceutical compositions) may be pharmaceutical (e.g., therapeutic or prophylactic), diagnostic, cosmetic, or nutraceutical agents. Any chemical compound to be administered to a subject or to be contacted with a tissue or cell may be delivered using the compositions, complexes, particles, micelles, or liposomes described herein. The agent may be a small molecule (e.g., a small organic molecule or small inorganic molecule), protein, peptide, polynucleotide, targeting agent, isotopically labeled chemical compound, vaccine, or immunological agent. The agent may be an agent useful in bioprocessing (e.g., intracellular manufacturing of proteins, such as a cell's bioprocessing of a commercially useful chemical or fuel). For example, intracellular delivery of an agent may be useful in bioprocessing by maintaining the cell's health and/or growth, e.g., in the manufacturing of proteins. Any chemical compound to be administered to a subject or contacted with a tissue or cell may be delivered to the subject, tissue, or cell using the compositions described herein.

(532) Exemplary agents that may be included in a composition described herein include, but are not limited to, small molecules, organometallic compounds, polynucleotides, proteins, peptides, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, small molecules linked to proteins, glycoproteins, steroids, nucleotides, oligonucleotides, polynucleotides, nucleosides, antisense oligonucleotides, lipids, hormones, vitamins, cells, metals, targeting agents, isotopically labeled chemical compounds, drugs (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations), vaccines, immunological agents, agents useful in bioprocessing, and mixtures thereof. The targeting agents are described in more detail herein. In certain embodiments, the agents are nutraceutical agents. In certain embodiments, the agents are pharmaceutical agents (e.g., a therapeutic or prophylactic agent). In certain embodiments, the agent is an antibiotic agent (e.g., an anti-bacterial, anti-viral, or anti-fungal agent), anesthetic, steroidal agent, anti-proliferative agent, anti-inflammatory agent, anti-angiogenesis agent, anti-neoplastic agent, anti-cancer agent, anti-diabetic agent, antigen, vaccine, antibody, decongestant, antihypertensive, sedative, birth control agent, progestational agent, anti-cholinergic, analgesic, immunosuppressant, anti-depressant, anti-psychotic, -adrenergic blocking agent, diuretic, cardiovascular active agent, vasoactive agent, non-steroidal, nutritional agent, anti-allergic agent, or pain-relieving agent. Vaccines may comprise isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically altered organisms or viruses, and cell extracts. Therapeutic and prophylactic agents may be combined with interleukins, interferon, cytokines, and adjuvants such as cholera toxin, alum, and Freund's adjuvant, etc.

(533) In certain embodiments, an agent to be delivered or used in a composition described herein is a polynucleotide. In certain embodiments, the agent is plasmid DNA (pDNA). In certain embodiments, the agent is single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, or viral DNA. In certain embodiments, the agent is RNA. In certain embodiments, the agent is small interfering RNA (siRNA). In certain embodiments, the agent is messenger RNA (mRNA). In certain embodiments, the agent is single-stranded RNA (ssRNA), double-stranded RNA (dsRNA), small interfering RNA (siRNA), precursor messenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal recognition particle RNA, small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA. In certain embodiments, the agent is an RNA that carries out RNA interference (RNAi). The phenomenon of RNAi is discussed in greater detail, for example, in the following references: Elbashir et al., 2001, Genes Dev., 15:188; Fire et al., 1998, Nature, 391:806; Tabara et al., 1999, Cell, 99:123; Hammond et al., Nature, 2000, 404:293; Zamore et al., 2000, Cell, 101:25; Chakraborty, 2007, Curr. Drug Targets, 8:469; and Morris and Rossi, 2006, Gene Ther., 13:553. In certain embodiments, upon delivery of an RNA into a subject, tissue, or cell, the RNA is able to interfere with the expression of a specific gene in the subject, tissue, or cell. In certain embodiments, the agent is a pDNA, siRNA, mRNA, or a combination thereof.

(534) In certain embodiments, the polynucleotide may be provided as an antisense agent or RNAi. See, e.g., Fire et al., Nature 391:806-811, 1998. Antisense therapy is meant to include, e.g., administration or in situ provision of single- or double-stranded polynucleotides, or derivatives thereof, which specifically hybridize, e.g., bind, under cellular conditions, with cellular mRNA and/or genomic DNA, or mutants thereof, so as to inhibit the expression of the encoded protein, e.g., by inhibiting transcription and/or translation. See, e.g., Crooke, Molecular mechanisms of action of antisense drugs, Biochim. Biophys. Acta 1489(1):31-44, 1999; Crooke, Evaluating the mechanism of action of anti-proliferative antisense drugs, Antisense Nucleic Acid Drug Dev. 10(2):123-126, discussion 127, 2000; Methods in Enzymology volumes 313-314, 1999. The binding may be by conventional base pair complementarity, or, for example, in the case of binding to DNA duplexes, through specific interactions in the major groove of the double helix (i.e., triple helix formation). See, e.g., Chan et al., J. Mol. Med. 75(4):267-282, 1997.

(535) The RNA and/or RNAi described herein can be designed and/or predicted using one or more of a large number of available algorithms. To give but a few examples, the following resources can be utilized to design and/or predict polynucleotides: algorithms found at Alnylum Online; Dharmacon Online; OligoEngine Online; Molecula Online; Ambion Online; BioPredsi Online; RNAi Web Online; Chang Bioscience Online; Invitrogen Online; LentiWeb Online GenScript Online; Protocol Online; Reynolds et al., 2004, Nat. Biotechnol., 22:326; Naito et al., 2006, Nucleic Acids Res., 34:W448; Li et al., 2007, RNA, 13:1765; Yiu et al., 2005, Bioinformatics, 21:144; and Jia et al., 2006, BMC Bioinformatics, 7: 271.

(536) The polynucleotide included in a composition described herein may be of any size or sequence, and they may be single- or double-stranded. In certain embodiments, the polynucleotide includes at least about 30, at least about 100, at least about 300, at least about 1,000, at least about 3,000, or at least about 10,000 base pairs. In certain embodiments, the polynucleotide includes less than about 10,000, less than about 3,000, less than about 1,000, less than about 300, less than about 100, or less than about 30 base pairs. Combinations of the above ranges (e.g., at least about 100 and less than about 1,000) are also within the scope of the disclosure. The polynucleotide may be provided by any suitable means known in the art. In certain embodiments, the polynucleotide is engineered using recombinant techniques. See, e.g., Ausubel et al., Current Protocols in Molecular Biology (John Wiley & Sons, Inc., New York, 1999); Molecular Cloning: A Laboratory Manual, 2nd Ed., ed. by Sambrook, Fritsch, and Maniatis (Cold Spring Harbor Laboratory Press: 1989). The polynucleotide may also be obtained from natural sources and purified from contaminating components found normally in nature. The polynucleotide may also be chemically synthesized in a laboratory. In certain embodiments, the polynucleotide is synthesized using standard solid phase chemistry. The polynucleotide may be isolated and/or purified. In certain embodiments, the polynucleotide is substantially free of impurities. In certain embodiments, the polynucleotide is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99% free of impurities.

(537) The polynucleotide may be modified by physical, chemical, and/or biological means. The modifications include methylation, phosphorylation, and/or end-capping, etc. In certain embodiments, the modifications lead to increased stability of the polynucleotide.

(538) Wherever a polynucleotide is employed in the present disclosure, a derivative of the polynucleotide may also be used. These derivatives include products resulted from modifications of the polynucleotide in the base moieties, sugar moieties, and/or phosphate moieties of the polynucleotide. Modified base moieties include, but are not limited to, 2-aminoadenosine, 2-thiothymidine, inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine, C5-bromouridine, C5-fluorouridine, C5-iodouridine, C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine, 7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine, O(6)-methylguanine, and 2-thiocytidine. Modified sugar moieties include, but are not limited to, 2-fluororibose, ribose, 2-deoxyribose, 3-azido-2,3-dideoxyribose, 2,3-dideoxyribose, arabinose (the 2-epimer of ribose), acyclic sugars, and hexoses. The nucleosides may be strung together by linkages other than the phosphodiester linkage found in naturally occurring DNA and RNA. Modified linkages include, but are not limited to, phosphorothioate and 5-N-phosphoramidite linkages. Combinations of the various modifications may be used in a single polynucleotide. These modified polynucleotides may be provided by any suitable means known in the art; however, as will be appreciated by those of skill in the art, the modified polynucleotides may be prepared using synthetic chemistry in vitro.

(539) The polynucleotide described herein may be in any form, such as a circular plasmid, a linearized plasmid, a cosmid, a viral genome, a modified viral genome, or an artificial chromosome.

(540) The polynucleotide described herein may be of any sequence. In certain embodiments, the polynucleotide encodes a protein or peptide. The encoded protein may be an enzyme, structural protein, receptor, soluble receptor, ion channel, active (e.g., pharmaceutically active) protein, cytokine, interleukin, antibody, antibody fragment, antigen, coagulation factor, albumin, growth factor, hormone, or insulin, etc. The polynucleotide may also comprise regulatory regions to control the expression of a gene. These regulatory regions may include, but are not limited to, promoters, enhancer elements, repressor elements, TATA boxes, ribosomal binding sites, and stop sites for transcription. In certain embodiments, the polynucleotide is not intended to encode a protein. For example, the polynucleotide may be used to fix an error in the genome of the cell being transfected.

(541) In certain embodiments, the polynucleotide described herein comprises a sequence encoding an antigenic peptide or protein. A composition containing the polynucleotide can be delivered to a subject to induce an immunologic response sufficient to decrease the chance of a subsequent infection and/or lessen the symptoms associated with such an infection. The polynucleotide of these vaccines may be combined with interleukins, interferon, cytokines, and/or adjuvants described herein.

(542) The antigenic protein or peptides encoded by the polynucleotide may be derived from bacterial organisms, such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptospirosis interrogans, Borrelia burgdorferi, and Camphylobacter jejuni; from viruses, such as smallpox virus, influenza A virus, influenza B virus, respiratory syncytial virus, parainfluenza virus, measles virus, HIV virus, varicella-zoster virus, herpes simplex 1 virus, herpes simplex 2 virus, cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus, adenovirus, papillomavirus, poliovirus, mumps virus, rabies virus, rubella virus, coxsackieviruses, equine encephalitis virus, Japanese encephalitis virus, yellow fever virus, Rift Valley fever virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus; and from fungal, protozoan, or parasitic organisms, such as Cryptococcus neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis, Plasmodium falciparum, Trypanosoma brucei, Entamoeba histolytica, Toxoplasma gondii, Trichomonas vaginalis, and Schistosoma mansoni.

(543) An agent described herein may be covalently or non-covalently (e.g., complexed or encapsulated) attached to a polymer described herein, or included in a composition described herein. In certain embodiments, upon delivery of the agent into a cell, the agent is able to interfere with the expression of a specific gene in the cell.

(544) In certain embodiments, an agent described herein may be a mixture of two or more agents that may be useful as, e.g., combination therapies. A composition including the mixture can be used to achieve a synergistic effect. In certain embodiments, the composition including the mixture can be used to improve the activity and/or bioavailability, reduce and/or modify the metabolism, inhibit the excretion, and/or modify the distribution of at least one of the two or more agents in a subject, tissue, or cell to which the mixture is administered or dosed. It will also be appreciated that the composition including the mixture may achieve a desired effect for the same disorder, and/or it may achieve different effects. The two or more agents in the mixture may be useful for treating and/or preventing a same disease or different diseases described herein.

(545) The compositions (e.g., pharmaceutical compositions) described herein can be administered concurrently with, prior to, or subsequent to the one or more agents (e.g., pharmaceutical agents). Each one of the agents may be administered at a dose and/or on a time schedule determined for that agent. The agents may also be administered together with each other and/or with the composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

(546) Targeting Agents

(547) Since it is often desirable to target a particular cell, collection of cells, or tissue, polymers described herein, and the compositions, complexes, liposomes, micelles, and particles thereof, may be modified to include targeting moieties or targeting agents. For example, the polymers may include a targeting moiety or targeting agent. The targeting agent may be included throughout a particle of a polymer described herein or may be only on the surface (e.g., outer or inner surface) of the particle. A targeting agent may be a protein, peptide, carbohydrate, glycoprotein, lipid, small molecule, or polynucleotide, and a targeting moiety may be a fragment of the targeting agent. The targeting moiety or targeting agent may be used to target specific cells or tissues or may be used to promote endocytosis or phagocytosis of the particle. The targeting moieties or targeting agents include the ones known in the art. See, e.g., Cotten et al., Methods Enzym. 217:618, 1993. Examples of the targeting moieties and targeting agents include, but are not limited to, antibodies, antibodies, proteins, peptides, carbohydrates, receptor ligands, sialic acid, aptamers, and fragments thereof. If a targeting agent is included throughout a particle, the targeting agent may be included in the mixture that is used to form the particle. If the targeting agent is only on the surface of a particle, the targeting agent may be associated with (e.g., by covalent or non-covalent (e.g., electrostatic, hydrophobic, hydrogen bonding, van der Waals, rt-t stacking) interactions) the formed particle using standard chemical techniques.

(548) Complexes of a Lipidoid and an Agent

(549) The present disclosure contemplates that the polymers described herein are useful in the delivery of an agent described herein to a subject, tissue, or cell. Without wishing to be bound by any particular theory, the polymers have several desirable properties that make a composition that includes the polymer and an agent suitable for delivering the agent to a subject, tissue, or cell. The desirable properties include: 1) the ability of the polymer to complex with and protect the agent that may otherwise be labile; 2) the ability of the polymer to buffer the pH in an endosome of the cell; 3) the ability of the polymer to act as a proton sponge and cause endosomolysis; and 4) the ability of the polymer to substantially neutralize the negative charges of the agent.

(550) A polymer and agent described herein may form a complex in a composition of the disclosure. For example, a polymer described herein comprises secondary or tertiary amino moieties, which may be useful in enhancing the ability of a composition that includes an agent to deliver the agent to a subject, tissue, or cell. The amino moieties, sterically hindered or not, may non-covalently interact with the agent, such as a polynucleotide. The agent may be contacted with the polymer under conditions suitable to form a complex. In certain embodiments, the agent binds to the polymer to form a complex through non-covalent interactions. In certain embodiments, the agent binds to the polymer to form a complex through electrostatic interactions. Without wishing to be bound by any particular theory, one or more amino moieties of a polymer described herein may be positively charged, and an agent described herein may be negatively charged (e.g., at the monophosphate, diphosphate, and/or triphosphate moieties of a polynucleotide), when the polymer, or a composition thereof, is delivered to a subject, tissue, or cell (e.g., under physiological conditions). The agent may bind to the polymer to form a complex through electrostatic interactions between the negative charges of the polymer and the positive charges of the agent. By substantially neutralizing the charges (e.g., negative charges) of the agent, the resulting complex may be able to more easily pass through the hydrophobic membranes (e.g., cytoplasmic, lysosomal, endosomal, or nuclear) of a cell, compared to an agent whose charges are not neutralized. In certain embodiments, the complex is substantially neutral. In certain embodiments, the complex is slightly positively charged. In certain embodiments, the complex has a positive -potential. In certain embodiments the -potential is between 0 and +30.

(551) An agent described herein, such as a polynucleotide, may be degraded chemically and/or enzymatically (e.g., by nucleases). The interaction of a polymer described herein with the agent is thought to at least partially prevent the degradation of the agent.

(552) A polymer described herein may be at least partially provided as a salt (e.g., being protonated) so as to form a complex with a negatively charged agent. In certain embodiments, the complex form particles that are useful in the delivery of the agent to a subject, tissue, or cell. In certain embodiments, more than one polymer described herein are associated with an agent. For example, the complex may include 1-10, 1-100, 1-1,000, 10-1,000, 100-1,000, or 100-10,000 polymers described herein associated with an agent.

(553) The ratio of the amount of a polymer described herein to the amount of an agent to be delivered in a described composition that includes the polymer and agent (e.g., as a complex) may be adjusted so that the agent may be more efficiently delivered to a subject, tissue, or cell and/or the toxicity of the composition is decreased. In certain embodiments, the ratio of the polymer to the agent is at least about 1:1, at least about 2:1, at least about 5:1, at least about 10:1, at least about 20:1, at least about 50:1, at least about 100:1, at least about 200:1, or at least about 500:1 mol/mol. In certain embodiments, the ratio of the polymer to the agent is less than about 500:1, less than about 200:1, less than about 100:1, less than about 50:1, less than about 20:1, less than about 10:1, less than about 5:1, less than about 2:1, or less than about 1:1 mol/mol. Combinations of the above ranges (e.g., at least about 10:1 and less than about 100:1) are also within the scope of the disclosure.

(554) The ratio of the amount of the amino moieties of a polymer described herein to the amount of the phosphate moieties of a polynucleotide (i.e., nitrogen:phosphate ratio) in a described composition that includes the polymer and polynucleotide (e.g., as a complex) may also be adjusted so that the polynucleotide may be more efficiently delivered to a subject, tissue, or cell and/or the toxicity of the composition is decreased. See, e.g., Incani et al., Soft Matter (2010) 6:2124-2138. In certain embodiments, the nitrogen:phosphate ratio is at least about 1:1, at least about 2:1, at least about 5:1, at least about 10:1, at least about 20:1, at least about 50:1, at least about 100:1, at least about 200:1, or at least about 500:1 mol/mol. In certain embodiments, the nitrogen:phosphate ratio is less than about 500:1, less than about 200:1, less than about 100:1, less than about 50:1, less than about 20:1, less than about 10:1, less than about 5:1, less than about 2:1, or less than about 1:1 mol/mol. Combinations of the above ranges (e.g., at least about 10:1 and less than about 100:1) are also within the scope of the disclosure.

(555) Particles

(556) A composition that includes a polymer and agent described herein may be in the form of a particle. In certain embodiments, the polymer is in the form of a particle. In certain embodiments, the agent is in the form of a particle. In certain embodiments, the polymer and agent form a complex, and the complex is in the form of a particle. In certain embodiments, the polymer encapsulates the agent and is in the form of a particle. In certain embodiments, the polymer is mixed with the agent, and the mixture is in the form of a particle.

(557) Encapsulation of an agent (e.g., a polynucleotide, such as an siRNA) within particles (e.g., nanoparticles) may offer numerous benefits for delivering the agent to a subject, tissue, or cell, including protection from degradation of the agent by ubiquitous nucleases, passive and active targeting, and/or evasion of endosomal Toll-like receptors. To date, several polymeric, lipid, and dendritic nanoparticles have been developed for the encapsulation and delivery of siRNAs. Despite the delivery successes met by some of these carriers, challenges to efficient delivery exist, including particle dissociation via serum proteins, cellular uptake, endosomal escape, and appropriate intracellular disassembly. To address some of these challenges, single parameter studies that evaluate the effect of chemical structure on a single biological property or on delivery performance have been reported. Furthermore, high-throughput synthetic methods have been exploited for the accelerated discovery of potent lipid nanoparticles (LNPs) and evaluation of structure activity relationships (SARs). In spite of these efforts, the relationships between physicochemical properties of nanoparticles and biological barriers, and that between biological barriers and gene silencing activity remain unclear. This lack of clarity has also resulted in poor in vitro-in vivo translation.

(558) In certain embodiments, a polymer described herein (e.g., a plurality of molecules of the polymer) is in the form of a particle. In certain embodiments, a complex of a polymer and agent described herein in a described composition is in the form of a particle. In certain embodiments, the particle is a microparticle. In certain embodiments, the particle is a nanoparticle. Such a nanoparticle may be referred to as a lipid nanoparticle (LNP). In certain embodiments, the average diameter of the particle is less than about 1 mm, less than about 300 m, less than about 100 m, less than about 30 m less than about 10 m, less than about 3 m, less than about 1 m, less than about 300 nm, less than about 100 nm, less than about 30 nm, or less than about 10 nm. In certain embodiments, the average diameter of the particle is at least about 10 nm, at least about 30 nm, at least about 100 nm, at least about 300 nm, at least about 1 m, at least about 3 m, at least about 10 m, at least about 30 m, at least about 100 m, at least about 300 m, or at least about 1 mm. Combinations of the above ranges (e.g., at least about 100 nm and less than about 1 m) are also within the scope of the present disclosure.

(559) In certain embodiments, a particle described herein includes an agent described herein. The particle may encapsulate the agent. A particle described herein may further include additional materials such as polymers (e.g., synthetic polymers (e.g., PEG, PLGA) and natural polymers (e.g., phospholipids, proteins)). In certain embodiments, the particle further includes a lipid (e.g., a steroid, a substituted or unsubstituted cholesterol, or a polyethylene glycol (PEG)-containing material). In certain embodiments, the additional materials are approved by a regulatory agency, such as the U.S. FDA, for human and/or veterinary use.

(560) A particle described herein may be prepared using any suitable method known in the art, such as precipitation, milling, spray drying, single and double emulsion solvent evaporation, solvent extraction, phase separation, and simple and complex coacervation. In certain embodiments, methods of preparing the particles are the double emulsion process and spray drying. The conditions used in preparing the particles may be altered to yield particles of a desired size or property (e.g., hydrophobicity, hydrophilicity, external morphology, stickiness, shape, and polydispersity). The method of preparing the particles and the conditions (e.g., solvent, temperature, concentration, and air flow rate) used may also depend on the agent being complexed, encapsulated, or mixed, and/or the composition of the matrix.

(561) Methods developed for making particles for delivery of agents that are included in the particles are described in the literature. See, e.g., Doubrow, M., Ed., Microcapsules and Nanoparticles in Medicine and Pharmacy, CRC Press, Boca Raton, 1992; Mathiowitz and Langer, J. Controlled Release 5:13-22, 1987; Mathiowitz et al., Reactive Polymers 6:275-283, 1987; Mathiowitz et al., J. Appl. Polymer Sci. 35:755-774, 1988.

(562) If the particles prepared by any of the methods described herein have a size range outside of the desired range, the particles can be sized, for example, using a sieve. The particles may also be coated. In certain embodiments, the particles are coated with a targeting agent. In certain embodiments, the particles are coated with a surface-altering agent. In some embodiments, the particles are coated to achieve desirable surface properties (e.g., a particular charge).

(563) Particles described herein may also be a micelle, liposome, or lipoplex.

(564) In certain embodiments, the polydispersity index (PDI, determined by dynamic light scattering) of the particles described herein (e.g., particles included in a composition described herein) is between 0.01 and 0.9, between 0.1 and 0.9, between 0.1 and 0.7, between 0.1 and 0.5, between 0.01 and 0.4, between 0.03 and 0.4, between 0.1 and 0.4, between 0.01 and 0.3, between 0.03 and 0.3, or between 0.1 and 0.3.

(565) Micelles, Liposomes, and Lipoplexes

(566) A composition including a polymer and agent described herein may be in the form of a micelle or liposome. In certain embodiments, the polymer is in the form of a micelle or liposome. An agent described herein may be inside a micelle or liposome, and a lipidoid described herein may be inside the micelle or liposome. In certain embodiments, in a micelle or liposome, an agent is encapsulated in a lipidoid. Micelles and liposomes are typically useful in delivering an agent, such as a hydrophobic agent, to a subject, tissue, or cell. When the micelle or liposome is complexed with (e.g., encapsulates or covers) a polynucleotide, the resulting complex may be referred to as a lipoplex. Many techniques for preparing micelles and liposomes are known in the art, and any such method may be used to make micelles and liposomes.

(567) In certain embodiments, liposomes are formed through spontaneous assembly. In some embodiments, liposomes are formed when thin lipid films or lipid cakes are hydrated and stacks of lipid crystalline bilayers become fluid and swell. The hydrated lipid sheets detach during agitation and self-close to form large, multilamellar vesicles (LMV). This may prevent interaction of water with the hydrocarbon core of the bilayers at the edges. Once these liposomes have formed, reducing the size of the liposomes can be modified through input of sonic energy (sonication) or mechanical energy (extrusion). See, e.g., Walde, P. Preparation of Vesicles (Liposomes) In Encylopedia of Nanoscience and Nanotechnology; Nalwa, H. S. Ed. American Scientific Publishers: Los Angeles, 2004; Vol. 9, pp. 43-79; Szoka et al., Comparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes) Ann. Rev. Biophys. Bioeng. 9:467-508, 1980; each of which is incorporated herein by reference. The preparation of lipsomes may involve preparing a polymer described herein for hydration, hydrating the polymer with agitation, and sizing the vesicles to achieve a homogenous distribution of liposomes. A polymer described herein may be first dissolved in a solvent in a container to result in a homogeneous mixture. The solvent is then removed to form a film. This film is thoroughly dried to remove residual amount of the solvent, e.g., by placing the container in vacuo for a period of time. Hydration of the film may be accomplished by adding an aqueous medium and agitating the resulting mixture. Disruption of LMV suspensions using sonic energy typically produces small unilamellar vesicles (SUV) with diameters in the range of 15-50 nm. Lipid extrusion is a technique in which a lipid suspension is forced through a polycarbonate filter with a defined pore size to yield particles having a diameter near the pore size of the filter used. Extrusion through filters with 100 nm pores typically yields large, unilamellar vesicles (LUV) with a mean diameter of 120-140 nm. In certain embodiments, the amount of a polymer described herein in the liposome is between about 30 mol % and about 80 mol %, between about 40 mol % and about 70 mol %, or between about 60 mol % and about 70 mol %, inclusive. In certain embodiments, the polymer further complexes an agent, such as a polynucleotide.

(568) Liposomes and micelles may also be prepared according to methods in the following scientific papers: Narang et al., Cationic Lipids with Increased DNA Binding Affinity for Nonviral Gene Transfer in Dividing and Nondividing Cells, Bioconjugate Chem. 16:156-68, 2005; Hofland et al., Formation of stable cationic lipid/DNA complexes for gene transfer, Proc. Natl. Acad. Sci. USA 93:7305-7309, July 1996; Byk et al., Synthesis, Activity, and StructureActivity Relationship Studies of Novel Cationic Lipids for DNA Transfer, J. Med. Chem. 41(2):224-235, 1998; Wu et al., Cationic Lipid Polymerization as a Novel Approach for Constructing New DNA Delivery Agents, Bioconjugate Chem. 12:251-57, 2001; Lukyanov et al., Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs, Advanced Drug Delivery Reviews 56:1273-1289, 2004; Tranchant et al., Physicochemical optimisation of plasmid delivery by cationic lipids, J. Gene Med. 6:S24-S35, 2004; van Balen et al., Liposome/Water Lipophilicity: Methods, Information Content, and Pharmaceutical Applications, Medicinal Research Rev. 24(3):299-324, 2004.

(569) Kits

(570) Also described herein are kits (e.g., packs). The kits provided may comprise a polymer or composition described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, a kit described herein further includes a second container comprising an excipient for dilution or suspension of a polymer or composition described herein. In some embodiments, the polymer or composition provided in the first container and the polymer or composition provided in the second container are combined to form one unit dosage form.

(571) In certain embodiments, the kits described herein are useful for delivering an agent to a subject, tissue, or cell. In certain embodiments, the kits are useful for delivering an agent to a target tissue described herein. In certain embodiments, the kits are useful for treating a disease described herein. In certain embodiments, the kits are useful for preventing a disease described herein.

(572) In certain embodiments, the described kits further include instructions for administering a polymer or composition described herein. The kits may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits, including the instructions, provide for delivering an agent described herein to a subject, tissue, or cell. In certain embodiments, the kits, including the instructions, provide for treating a disease described herein. In certain embodiments, the kits, including the instructions, provide for preventing a disease described herein. The kit described herein may include one or more agents described herein as a separate composition.

(573) Methods of Treatment and Uses

(574) It is estimated that over 10,000 human diseases are caused by genetic disorders, which are abnormalities in genes or chromosomes. See, e.g., McClellan, J. and M. C. King, Genetic heterogeneity in human disease. Cell. 141(2): p. 210-7; Leachman, S. A., et al., J. Dermatol. Sci., 2008. 51(3): p. 151-7. Many of these diseases are fatal, such as cancer, severe hypercholesterolemia, and familial amyloidotic polyneuropathy. See, e.g., Frank-Kamenetsky, M., et al., Proc. Natl. Acad. Sci. U.S.A. 2008. 105(33): p. 11915-20; Coelho, T., Curr. Opin. Neurol., 1996. 9(5): p. 355-9. Since the discovery of gene expression silencing via RNA interference (RNAi) by Fire and Mello (Fire, A., et al., Nature, 1998. 391(6669): p. 806-11), there has been extensive effort toward developing therapeutic applications for RNAi in humans. See, e.g., Davis, M. E., Mol. Pharm. 2009. 6(3): p. 659-68; Whitehead, K. A., R. Langer, and D. G. Anderson, Nat. Rev. Drug Discovery, 2009. 8(2): p. 129-138; Tan, S. J., et al., Small. 7(7): p. 841-56; Castanotto, D. and J. J. Rossi, Nature, 2009. 457(7228): p. 426-33; Chen, Y. and L. Huang, Expert Opin. Drug Deliv. 2008. 5(12): p. 1301-11; Weinstein, S. and D. Peer, Nanotechnology. 21(23): p. 232001; Fenske, D. B. and P. R. Cullis, Expert Opin. Drug Deliv. 2008. 5(1): p. 25-44; and Thiel, K. W. and P. H. Giangrande, Oligonucleotides, 2009. 19(3): p. 209-22. Currently, there are more than 20 clinical trials ongoing or completed involving siRNA therapeutics, which have shown promising results for the treatment of various diseases. See, e.g., Burnett, J. C., J. J. Rossi, and K. Tiemann, Biotechnol. J. 6(9): p. 1130-46. However, the efficient and safe delivery of siRNA is still a key challenge in the development of siRNA therapeutics. See, e.g., Juliano, R., et al., Mol. Pharm. 2009. 6(3): p. 686-95.

(575) In another aspect, the present disclosure provides methods of delivering an agent described herein (e.g., polynucleotide) to a subject, tissue, or cell. In certain embodiments, described herein are methods of delivering the agent to a target tissue or target cell described herein. In certain embodiments, described herein are methods of selectively delivering the agent to a target tissue, compared to a non-target tissue. In certain embodiments, described herein are methods of selectively delivering the agent to a target cell, compared to a non-target cell. In certain embodiments, the agent is delivered into the subject, tissue, or cell by the methods described herein. In certain embodiments, the agent is selectively delivered into the target tissue or target cell by the methods described herein, compared to a non-target tissue or non-target cell, respectively.

(576) Another aspect of the present disclosure relates to methods of increasing the delivery of an agent to a subject, tissue, or cell. In certain embodiments, the delivery of the agent to the subject, tissue, or cell is increased by a method described herein. In certain embodiments, the delivery of the agent to the subject, tissue, or cell by a method described herein is increased compared to the delivery of the agent to the subject, tissue, or cell by a control method that does not involve a polymer described herein.

(577) In another aspect, the present disclosure provides methods of treating a disease described herein in a subject in need thereof.

(578) In another aspect, the present disclosure provides methods of preventing a disease described herein in a subject in need thereof.

(579) In certain embodiments, a disease described herein is a genetic disease. In certain embodiments, the disease is a proliferative disease. In certain embodiments, the disease is cancer. In certain embodiments, the disease is a benign neoplasm. In certain embodiments, the disease is pathological angiogenesis. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is an autoimmune disease. In certain embodiments, the disease is a hematological disease. In certain embodiments, the disease is a neurological disease. In certain embodiments, the disease is a gastrointestinal disease. In certain embodiments, the disease is a liver disease. In certain embodiments, the disease is a spleen disease. In certain embodiments, the disease is a respiratory disease. In certain embodiments, the disease is a lung disease. In certain embodiments, the disease is a painful condition. In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition is associated with an inflammatory disorder and/or an autoimmune disorder. In certain embodiments, the disease is a psychiatric disorder. In certain embodiments, the disease is a musculoskeletal disease. In certain embodiments, the disease is a genitourinary disease. In certain embodiments, the disease is a metabolic disorder.

(580) Another aspect of the present disclosure relates to methods of genetically engineering a subject. In certain embodiments, the subject is genetically engineered to increase the growth of the subject. In certain embodiments, the subject is genetically engineered to increase the subject's resistance to pathogenic organisms and/or microorganisms (e.g., viruses, bacteria, fungi, protozoa, and parasites).

(581) In certain embodiments, a method described herein includes administering to the subject a composition described herein. In certain embodiments, a method described herein includes administering to the subject an effective amount of a composition described herein. In certain embodiments, a method described herein includes administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein.

(582) In certain embodiments, a method described herein includes contacting the tissue with a composition described herein. In certain embodiments, a method described herein includes contacting the tissue with an effective amount of a composition described herein. In certain embodiments, a method described herein includes contacting the tissue with a therapeutically effective amount of a pharmaceutical composition described herein.

(583) In certain embodiments, a method described herein includes contacting the cell with a composition described herein. In certain embodiments, a method described herein includes contacting the cell with an effective amount of a composition described herein. In certain embodiments, a method described herein includes contacting the cell with a therapeutically effective amount of a pharmaceutical composition described herein.

(584) In certain embodiments, a subject described herein is a human. In certain embodiments, the subject is an animal. In certain embodiments, the subject is a non-human animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a fish. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal. In certain embodiments, the subject is a human with a disease described herein. In certain embodiments, the subject is a human suspected of having a disease described. In certain embodiments, the subject is a human at risk of developing a disease described herein.

(585) In certain embodiments, a cell described herein is in vivo. In certain embodiments, a cell described herein is in vitro.

(586) Another aspect of the present disclosure relates to methods of screening a library of polymers to identify a polymer that is useful in the methods described herein. In certain embodiments, the methods of screening a library of polymers are useful in identifying a polymer with desired or undesired properties. In certain embodiments, the desired property is solubility in water, solubility at different pH, ability to bind polynucleotides, ability to bind heparin, ability to bind small molecules, ability to bind protein, ability to form microparticles, ability to increase transfection efficiency, ability to support normal cell growth, ability to inhibit abnormal cell growth, ability to support cell attachment, ability to support tissue growth, and/or intracellular delivery of an agent described herein and/or an agent complexed or attached thereto to aid in bioprocessing. In certain embodiments, the undesired property is the lack of a desired property. In certain embodiments, the polymer identified is useful for delivering an agent described herein to a subject, tissue, or cell. In certain embodiments, the polymer identified is useful for treating and/or preventing a disease described herein. In certain embodiments, the library of polymers is a library of polymers described herein. In certain embodiments, the methods of screening a library include providing at least two different polymers described herein; and performing at least one assay using the polymers. In certain embodiments, at least one assay is useful in identifying a polymer that is useful in a method described herein. The assay may be an immunoassay, such as a sandwich-type assay, competitive binding assay, one-step direct test, two-step test, or blot assay. The step of performing at least one assay may be performed robotically or manually.

(587) Another aspect of the present disclosure relates to uses of a polymer described herein in a method described herein (e.g., uses for delivering an agent to a subject, tissue, or cell; uses for treating a disease in a subject in need thereof; and uses for preventing a disease in a subject).

(588) Another aspect of the present disclosure relates to uses of a composition described herein (e.g., a composition including a described polymer, agent, and optionally a pharmaceutical excipient) in a method described herein (e.g., uses for delivering an agent to a subject, tissue, or cell; uses for treating a disease in a subject in need thereof; and uses for preventing a disease in a subject).

EXAMPLES

(589) In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the polymers, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1. Preparation of the Polymers

(590) Reineke and co-workers previously reported on the development of poly(glycoamidoamines) (PGAAs), which contain amines and multiple hydroxyl groups along their polymer backbone. These polymers previously demonstrated efficient delivery of both DNA and siRNA in different cell types..sup.11-13, 15, 16 Beginning with the PGAA polymer backbone,.sup.16-18 we prepared modified PGAAs to create new polymer-brush materials for incorporation into lipid nanoparticle formulations. First, we synthesized three different PGAA polymers based on tartarate, galactarate, or glucarate sugars combined with three different amine-containing monomers using the synthetic methods reported by Reineke..sup.11-14 1HNMR of PGAA polymers is consistent with reported data. Next, alkyl tails were added onto amines on the PGAA backbone using ring opening reactions with epoxides to afford a modified polymer-brush materials..sup.18-21 Structures of polymers were confirmed by .sup.1HNMR and their molecular weight was calculated based on the results reported by Reineke and .sup.1HNMR of final products..sup.12 The nomenclature for polymer identification signifies the combination of these three structural building blocks; a three letter code (Tartartarate, Galgalactarate, or Gluglucarate) denoting the sugar used to prepare the PGAA backbone followed by the number of amines in the amine-containing monomer (N1, N2, or N3), and finally the number of carbons (C8, C10, C12, C14, or C16) on the epoxides used for modification.

(591) The polymers provided herein can be prepared from readily available starting materials using the following general methods and procedures (e.g., the method shown in Scheme 1, 2, or 3). It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization.

(592) ##STR00442##

(593) In an exemplary reaction, a mixture of a polymer of Formula (A1) and an epoxide of Formula (A2) in a suitable solvent (e.g., EtOH) was heated in a microwave reactor at 150 C. for 5 h. The resulting reaction mixture was purified by flash chromatography to yield the desired polymer of Formula (I) (e.g., a polymer in Table 7).

(594) ##STR00443##

(595) ##STR00444##
General Methods and Materials

(596) Microwave irradiations were performed in a BIOTAGE INITIATOR. .sup.1H NMR spectra were measured on a 300 & 500 MHz VARIAN spectrometer using TMS as internal standard. Mass spectra were measured on a WATERS ACQUITY LC-MS instrument. Thin-layer chromatography (TLC) was performed on precoated silica gel GF plates purchased from Merck, Inc. ISCO COMBIFLASH systems were used for flash chromatography. All other chemicals were obtained from commercial sources and were used as received.

(597) An exemplary preparation of the polymers described herein was through ring opening reactions between poly(glycoamidoamine) (PGAAs) and epoxides. TarN, GalN, and GluN were synthesized using the methods reported by Reineke..sup.11-14 1HNMR of PGAA polymers is consistent with reported data..sup.11, 14 Different analytical data are shown below when different batches of a polymer was characterized.

(598) Polymers of any one of Formulae (I) and (I) can be prepared using methods similar to the methods of preparing the polymers of Formula (I). Polymers of any one of Formulae (II) and (II) can be prepared using methods similar to the methods of preparing the polymers of Formula (II). Polymers of any one of Formulae (III) and (III) can be prepared using methods similar to the methods of preparing the polymers of Formula (III).

(599) Polymer Alo

(600) .sup.1HNMR (500 MHz, D.sub.2O): 4.53 (s, 2H), 3.28-3.50 (m, 4H), 2.65-2.80 (m, 4H).

(601) Polymer A1b

(602) .sup.1HNMR (500 MHz, D.sub.2O): 4.51 (s, 2H), 3.28-3.57 (m, 4H), 2.63-2.85 (m, 8H).

(603) Polymer A1c

(604) .sup.1HNMR (500 MHz, D.sub.2O): 4.52 (s, 2H), 3.28-3.47 (m, 4H), 2.65-2.81 (m, 12H).

(605) Polymer A1p

(606) .sup.1HNMR (500 MHz, D.sub.2O): 4.41 (s, 2H), 4.00 (s, 2H), 3.31-3.48 (m, 4H), 2.71-2.80 (m, 4H).

(607) Polymer A1q

(608) .sup.1HNMR (500 MHz, D.sub.2O): 4.40 (m, 2H), 4.00 (s, 2H), 3.31-3.43 (m, 4H), 2.69-2.79 (m, 8H).

(609) Polymer A1r

(610) .sup.1HNMR (500 MHz, D.sub.2O): 4.35-4.43 (m, 2H), 3.92-4.04 (m, 2H), 3.30-3.47 (m, 4H), 2.65-2.85 (m, 12H).

(611) Polymer A1s

(612) .sup.1HNMR (500 MHz, D.sub.2O): 4.34-4.39 (m, 1H), 4.21-4.29 (m, 1H), 4.07-4.13 (m, 1H), 3.92-3.98 (t, 1H), 3.36-3.54 (m, 4H), 2.80-2.99 (m, 4H).

(613) Polymer A1t

(614) .sup.1HNMR (500 MHz, D.sub.2O): 4.29-4.38 (m, 1H), 4.22-4.26 (m, 1H), 4.06-4.13 (m, 1H), 3.91-3.99 (t, 1H), 3.30-3.55 (m, 4H), 2.73-2.98 (m, 8H).

(615) Polymer A1u

(616) .sup.1HNMR (500 MHz, D.sub.2O): 4.18-4.38 (m, 2H), 4.02-4.12 (m, 1H), 3.87-3.98 (m, 1H), 3.23-3.53 (m, 4H), 2.74-2.96 (m, 12H).

(617) Polymer TarN1C8

(618) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.10 (s, 1H), 3.96-4.91 (m, 3H), 3.21-3.8 (m, 4H), 2.06-3.15 (m, 6H), 1.15-1.37 (m, 14H), 0.79-0.94 (t, 3H).

(619) Polymer TarN1C10

(620) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.08 (s, 1H), 3.22-5.40 (m, 7H), 2.09-3.05 (m, 6H), 1.18-1.50 (m, 18H), 0.82-0.95 (t, 3H).

(621) Polymer TarN1C12

(622) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.10 (s, 1H), 3.87-4.98 (m, 3H), 3.09-3.86 (m, 4H), 1.98-3.04 (m, 6H), 1.17-1.52 (m, 22H), 0.79-0.94 (t, 3H).

(623) Polymer TarN1C14

(624) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.08 (s, 1H), 3.91-4.96 (m, 3H), 3.09-3.90 (m, 4H), 2.00-3.06 (m, 6H), 1.14-1.52 (m, 26H), 0.78-0.95 (t, 3H).

(625) Polymer TarN2C8

(626) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.02 (s, 1H), 3.98-4.79 (m, 4H), 3.40-3.84 (m, 4H), 2.02-3.02 (m, 12H), 1.16-1.55 (m, 28H), 0.79-0.96 (t, 6H).

(627) Polymer TarN2C10

(628) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.96 (s, 1H), 4.00-4.83 (m, 4H), 3.40-3.84 (m, 4H), 2.19-3.06 (m, 12H), 1.18-1.52 (m, 36H), 0.78-0.94 (t, 6H).

(629) Polymer TarN2C12

(630) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.90-8.23 (br, 1H), 4.00-4.87 (m, 4H), 3.40-3.84 (m, 4H), 2.09-3.02 (m, 12H), 1.17-1.51 (m, 44H), 0.79-0.95 (t, 6H).

(631) Polymer TarN2C14

(632) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.88-8.25 (br, 1H), 3.99-4.80 (m, 4H), 3.24-3.87 (m, 4H), 2.14-3.02 (m, 12H), 1.17-1.52 (m, 52H), 0.82-0.94 (t, 6H).

(633) Polymer TarN3C8

(634) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.05 (s, 1H), 3.30-3.80 (m, 9H), 2.02-2.98 (m, 18H), 1.17-1.52 (m, 42H), 0.83-0.96 (t, 9H).

(635) Polymer TarN3C10

(636) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.84-8.15 (br, 1H), 3.95-4.95 (m, 5H), 3.47-3.80 (m, 4H), 2.15-3.01 (m, 18H), 1.16-1.51 (m, 54H), 0.79-0.93 (t, 9H).

(637) Polymer TarN3C12

(638) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.88-8.19 (br, 1H), 3.93-4.67 (m, 5H), 3.45-3.76 (m, 4H), 2.20-2.97 (m, 18H), 1.18-1.50 (m, 66H), 0.78-0.95 (t, 9H).

(639) Polymer TarN3C14

(640) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.88-8.14 (br, 1H), 4.00-4.66 (m, 5H), 3.47-3.76 (m, 4H), 2.16-2.93 (m, 18H), 1.19-1.50 (m, 78H), 0.82-0.95 (t, 9H).

(641) Polymer TarN4C8

(642) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.92-8.07 (br, 1H), 4.20-4.91 (m, 6H), 3.50-3.75 (m, 4H), 2.01-3.07 (m, 26H), 1.18-1.52 (m, 56H), 0.82-0.98 (t, 12H).

(643) Polymer TarN4C10

(644) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.97-8.13 (br, 1H), 4.00-4.77 (m, 6H), 3.45-3.80 (m, 4H), 1.98-3.21 (m, 26H), 1.03-1.58 (m, 72H), 0.78-0.96 (t, 12H).

(645) Polymer TarN4C12

(646) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.08 (s, 1H), 3.51-3.82 (m, 4NHCO, 4-6OH), 2.07-2.97 (m, 26H), 1.18-1.52 (m, 88H), 0.82-0.96 (t, 12H).

(647) Polymer TarN4C14

(648) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.05 (s, 1H), 3.38-3.85 (m, 10H), 2.18-2.92 (m, 26H), 1.17-1.49 (m, 104H), 0.82-0.96 (t, 12H).

(649) Polymer GalN2C8

(650) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.00 (s, 1H), 3.18-4.76 (m, 10H), 2.19-3.05 (m, 12H), 1.17-1.50 (m, 28H), 0.81-0.91 (t, 6H).

(651) Polymer GalN2C10

(652) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.00 (s, 1H), 3.19-4.99 (m, 10H), 2.21-3.03 (m, 12H), 1.12-1.54 (m, 36H), 0.82-0.95 (t, 6H).

(653) Polymer GalN2C12

(654) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.01 (s, 1H), 3.97-5.19 (m, 6H), 3.41-3.84 (m, 4H), 2.20-3.04 (m, 12H), 1.16-1.52 (m, 44H), 0.84-0.95 (t, 6H).

(655) Polymer GalN2C14

(656) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.98 (s, 1H), 4.27-5.06 (m, 6H), 3.51-3.86 (m, 4H), 2.26-3.05 (m, 12H), 1.19-1.56 (m, 52H), 0.82-1.00 (t, 6H).

(657) Polymer GalN3C8

(658) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.95-8.21 (br, 1H), 3.25-4.78 (m, 11H), 2.15-2.94 (m, 18H), 1.18-1.52 (m, 42H), 0.82-0.93 (t, 9H).

(659) Polymer GalN3C10

(660) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.03 (s, 1H), 3.44-4.77 (m, 11H), 2.22-2.95 (m, 18H), 1.19-1.55 (m, 54H), 0.82-0.96 (t, 9H).

(661) Polymer GalN3C12

(662) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.99 (s, 1H), 3.37-3.94 (m, 11H), 2.25-2.97 (m, 18H), 1.16-1.54 (m, 66H), 0.84-0.96 (t, 9H).

(663) Polymer GalN3C14

(664) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.99 (s, 1H), 3.17-4.22 (m, 11H), 2.15-2.91 (m, 18H), 1.15-1.58 (m, 78H), 0.79-0.94 (t, 9H).

(665) Polymer GalN4C8

(666) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.03 (s, 1H), 3.45-5.15 (m, 12H), 2.09-2.98 (m, 24H), 1.18-1.53 (m, 56H), 0.81-0.97 (t, 12H).

(667) Polymer GalN4C10

(668) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.02 (s, 1H), 3.34-4.46 (m, 12H), 2.16-2.99 (m, 24H), 1.19-1.53 (m, 72H), 0.82-0.94 (t, 12H).

(669) Polymer GalN4C12

(670) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.02 (s, 1H), 3.34-4.34 (m, 12H), 2.10-2.97 (m, 24H), 1.19-1.53 (m, 88H), 0.81-0.94 (t, 12H).

(671) Polymer GalN4C14

(672) .sup.1HNMR (500 MHz, CDCl.sub.3): 7.99 (s, 1H), 3.43-4.31 (m, 12H), 2.09-2.98 (m, 24H), 1.18-1.51 (m, 104H), 0.84-0.95 (t, 12H).

(673) Polymer GluN1C10

(674) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.09 (s, 1H), 3.14-4.53 (m, 9H), 2.09-3.00 (m, 6H), 1.20-1.54 (m, 18H), 0.80-0.97 (t, 3H).

(675) Polymer GluN1C12

(676) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.10 (s, 1H), 3.10-4.75 (m, 9H), 2.01-2.99 (m, 6H), 1.17-1.54 (m, 22H), 0.82-0.95 (t, 3H).

(677) Polymer GluN1C14

(678) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.01 (s, 1H), 3.09-4.85 (m, 9H), 2.11-3.00 (m, 6H), 1.18-1.53 (m, 26H), 0.82-0.94 (t, 3H).

(679) Polymer GluN2C8

(680) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.06 (s, 1H), 3.09-4.45 (m, 10H), 2.22-3.00 (m, 12H), 1.16-1.49 (m, 28H), 0.82-0.93 (t, 6H).

(681) Polymer GluN2C10

(682) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.04 (s, 1H), 3.21-4.84 (m, 10H), 2.11-3.12 (m, 12H), 1.22-1.54 (m, 36H), 0.85-0.97 (t, 6H).

(683) Polymer GluN2C12

(684) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.06 (s, 1H), 3.07-4.82 (m, 10H), 2.00-3.00 (m, 12H), 1.05-1.82 (m, 44H), 0.78-1.01 (t, 6H).

(685) Polymer GluN2C14

(686) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.08 (s, 1H), 3.20-4.40 (m, 10H), 2.06-3.10 (m, 12H), 1.15-1.82 (m, 52H), 0.79-1.04 (t, 6H).

(687) Polymer GluN3C6

(688) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.06 (s, 1H), 3.31-4.80 (m, 11H), 1.98-3.12 (m, 18H), 1.15-1.62 (m, 30H), 0.83-1.06 (t, 9H).

(689) Polymer GluN3C8

(690) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.02 (s, 1H), 3.12-4.31 (m, 11H), 2.22-3.01 (m, 18H), 1.14-1.50 (m, 42H), 0.77-0.92 (t, 9H).

(691) Polymer GluN3C10

(692) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.05 (s, 1H), 3.33-4.38 (m, 11H), 2.02-3.05 (m, 18H), 1.16-1.58 (m, 54H), 0.79-0.98 (t, 9H).

(693) Polymer GluN3C12

(694) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.01 (s, 1H), 3.15-4.53 (m, 11H), 1.89-3.04 (m, 18H), 1.16-1.53 (m, 66H), 0.83-0.94 (t, 9H).

(695) Polymer GluN3C14

(696) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.04 (s, 1H), 3.20-4.09 (m, 11H), 2.13-3.00 (m, 18H), 1.17-1.51 (m, 78H), 0.81-0.95 (t, 9H).

(697) Polymer GluN4C8

(698) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.04 (s, 1H), 3.35-4.33 (m, 12H), 1.99-3.10 (m, 24H), 1.18-1.53 (m, 56H), 0.81-0.94 (t, 12H).

(699) Polymer GluN4C10

(700) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.00 (s, 1H), 3.43-4.34 (m, 12H), 2.02-3.07 (m, 24H), 1.16-1.54 (m, 72H), 0.80-0.93 (t, 12H).

(701) Polymer GluN4C12

(702) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.01 (s, 1H), 3.09-4.16 (m, 12H), 2.06-2.92 (m, 24H), 1.18-1.56 (m, 88H), 0.81-0.94 (t, 12H).

(703) Polymer GluN4C14

(704) .sup.1HNMR (500 MHz, CDCl.sub.3): 8.01 (s, 1H), 3.18-4.22 (m, 12H), 2.16-2.95 (m, 24H), 1.07-1.54 (m, 104H), 0.79-0.96 (t, 12H).

(705) Polymer TarN1C10

(706) .sup.1HNMR (500 MHz, CDCl3): 8.10 (s, 1H), 3.96-4.91 (m, 3H), 3.21-3.8 (m, 4H), 2.06-3.15 (m, 6H), 1.15-1.37 (m, 14H), 0.79-0.94 (t, 3H).

(707) Polymer TarN2C10

(708) .sup.1HNMR (500 MHz, CDCl3): 8.02 (s, 1H), 3.98-4.79 (m, 4H), 3.40-3.84 (m, 4H), 2.02-3.02 (m, 12H), 1.16-1.55 (m, 28H), 0.79-0.96 (t, 6H).

(709) Polymer TarN3C10

(710) .sup.1HNMR (500 MHz, CDCl3): 8.05 (s, 1H), 3.30-3.80 (m, 9H), 2.02-2.98 (m, 18H), 1.17-1.52 (m, 42H), 0.83-0.96 (t, 9H).

(711) Polymer TarN1C12

(712) .sup.1HNMR (500 MHz, CDCl3): 8.08 (s, 1H), 3.22-5.40 (m, 7H), 2.09-3.05 (m, 6H), 1.18-1.50 (m, 18H), 0.82-0.95 (t, 3H).

(713) Polymer TarN2C12

(714) .sup.1HNMR (500 MHz, CDCl3): 7.96 (s, 1H), 4.00-4.83 (m, 4H), 3.40-3.84 (m, 4H), 2.19-3.06 (m, 12H), 1.18-1.52 (m, 36H), 0.78-0.94 (t, 6H).

(715) Polymer TarN3C12

(716) .sup.1HNMR (500 MHz, CDCl3): 7.84-8.15 (br, 1H), 3.95-4.95 (m, 5H), 3.47-3.80 (m, 4H), 2.15-3.01 (m, 18H), 1.16-1.51 (m, 54H), 0.79-0.93 (t, 9H).

(717) Polymer TarN1C14

(718) .sup.1HNMR (500 MHz, CDCl3): 8.10 (s, 1H), 3.87-4.98 (m, 3H), 3.09-3.86 (m, 4H), 1.98-3.04 (m, 6H), 1.17-1.52 (m, 22H), 0.79-0.94 (t, 3H).

(719) Polymer TarN2C14

(720) .sup.1HNMR (500 MHz, CDCl3): 7.90-8.23 (br, 1H), 4.00-4.87 (m, 4H), 3.40-3.84 (m, 4H), 2.09-3.02 (m, 12H), 1.17-1.51 (m, 44H), 0.79-0.95 (t, 6H).

(721) Polymer TarN3C14

(722) .sup.1HNMR (500 MHz, CDCl3): 7.88-8.19 (br, 1H), 3.93-4.67 (m, 5H), 3.45-3.76 (m, 4H), 2.20-2.97 (m, 18H), 1.18-1.50 (m, 66H), 0.78-0.95 (t, 9H).

(723) Polymer TarN1C16

(724) .sup.1HNMR (500 MHz, CDCl3): 8.08 (s, 1H), 3.91-4.96 (m, 3H), 3.09-3.90 (m, 4H), 2.00-3.06 (m, 6H), 1.14-1.52 (m, 26H), 0.78-0.95 (t, 3H).

(725) Polymer TarN2C16

(726) .sup.1HNMR (500 MHz, CDCl3): 7.88-8.25 (br, 1H), 3.99-4.80 (m, 4H), 3.24-3.87 (m, 4H), 2.14-3.02 (m, 12H), 1.17-1.52 (m, 52H), 0.82-0.94 (t, 6H).

(727) Polymer TarN3C16

(728) .sup.1HNMR (500 MHz, CDCl3): 7.88-8.14 (br, 1H), 4.00-4.66 (m, 5H), 3.47-3.76 (m, 4H), 2.16-2.93 (m, 18H), 1.19-1.50 (m, 78H), 0.82-0.95 (t, 9H).

(729) Polymer GalN2C10

(730) .sup.1HNMR (500 MHz, CDCl3): 8.00 (s, 1H), 3.18-4.76 (m, 10H), 2.19-3.05 (m, 12H), 1.17-1.50 (m, 28H), 0.81-0.91 (t, 6H).

(731) Polymer GalN3C10

(732) .sup.1HNMR (500 MHz, CDCl3): 7.95-8.21 (br, 1H), 3.25-4.78 (m, 11H), 2.15-2.94 (m, 18H), 1.18-1.52 (m, 42H), 0.82-0.93 (t, 9H).

(733) Polymer GalN2C12

(734) .sup.1HNMR (500 MHz, CDCl3): 8.00 (s, 1H), 3.19-4.99 (m, 10H), 2.21-3.03 (m, 12H), 1.12-1.54 (m, 36H), 0.82-0.95 (t, 6H).

(735) Polymer GalN3C12

(736) .sup.1HNMR (500 MHz, CDCl3): 8.03 (s, 1H), 3.44-4.77 (m, 11H), 2.22-2.95 (m, 18H), 1.19-1.55 (m, 54H), 0.82-0.96 (t, 9H).

(737) Polymer GalN2C14

(738) .sup.1HNMR (500 MHz, CDCl3): 8.01 (s, 1H), 3.97-5.19 (m, 6H), 3.41-3.84 (m, 4H), 2.20-3.04 (m, 12H), 1.16-1.52 (m, 44H), 0.84-0.95 (t, 6H).

(739) Polymer GalN3C14

(740) .sup.1HNMR (500 MHz, CDCl3): 7.99 (s, 1H), 3.37-3.94 (m, 11H), 2.25-2.97 (m, 18H), 1.16-1.54 (m, 66H), 0.84-0.96 (t, 9H).

(741) Polymer GalN2C16

(742) .sup.1HNMR (500 MHz, CDCl3): 7.98 (s, 1H), 4.27-5.06 (m, 6H), 3.51-3.86 (m, 4H), 2.26-3.05 (m, 12H), 1.19-1.56 (m, 52H), 0.82-1.00 (t, 6H).

(743) Polymer GalN3C16

(744) .sup.1HNMR (500 MHz, CDCl3): 7.99 (s, 1H), 3.17-4.22 (m, 11H), 2.15-2.91 (m, 18H), 1.15-1.58 (m, 78H), 0.79-0.94 (t, 9H).

(745) Polymer GluN2C10

(746) .sup.1HNMR (500 MHz, CDCl3): 8.06 (s, 1H), 3.09-4.45 (m, 10H), 2.22-3.00 (m, 12H), 1.16-1.49 (m, 28H), 0.82-0.93 (t, 6H).

(747) Polymer GluN3C10

(748) .sup.1HNMR (500 MHz, CDCl3): 8.02 (s, 1H), 3.12-4.31 (m, 11H), 2.22-3.01 (m, 18H), 1.14-1.50 (m, 42H), 0.77-0.92 (t, 9H).

(749) Polymer GluN1C12

(750) .sup.1HNMR (500 MHz, CDCl3): 8.09 (s, 1H), 3.14-4.53 (m, 9H), 2.09-3.00 (m, 6H), 1.20-1.54 (m, 18H), 0.80-0.97 (t, 3H).

(751) Polymer GluN2C12

(752) .sup.1HNMR (500 MHz, CDCl3): 8.04 (s, 1H), 3.21-4.84 (m, 10H), 2.11-3.12 (m, 12H), 1.22-1.54 (m, 36H), 0.85-0.97 (t, 6H).

(753) Polymer GluN3C12

(754) .sup.1HNMR (500 MHz, CDCl3): 8.05 (s, 1H), 3.33-4.38 (m, 11H), 2.02-3.05 (m, 18H), 1.16-1.58 (m, 54H), 0.79-0.98 (t, 9H).

(755) Polymer GluN1C14

(756) .sup.1HNMR (500 MHz, CDCl3): 8.10 (s, 1H), 3.10-4.75 (m, 9H), 2.01-2.99 (m, 6H), 1.17-1.54 (m, 22H), 0.82-0.95 (t, 3H).

(757) Polymer GluN2C14

(758) .sup.1HNMR (500 MHz, CDCl3): 8.06 (s, 1H), 3.07-4.82 (m, 10H), 2.00-3.00 (m, 12H), 1.05-1.82 (m, 44H), 0.78-1.01 (t, 6H).

(759) Polymer GluN3C14

(760) .sup.1HNMR (500 MHz, CDCl3): 8.01 (s, 1H), 3.15-4.53 (m, 11H), 1.89-3.04 (m, 18H), 1.16-1.53 (m, 66H), 0.83-0.94 (t, 9H).

(761) Polymer GluN1C16

(762) .sup.1HNMR (500 MHz, CDCl3): 8.01 (s, 1H), 3.09-4.85 (m, 9H), 2.11-3.00 (m, 6H), 1.18-1.53 (m, 26H), 0.82-0.94 (t, 3H).

(763) Polymer GluN2C16

(764) .sup.1HNMR (500 MHz, CDCl3): 8.08 (s, 1H), 3.20-4.40 (m, 10H), 2.06-3.10 (m, 12H), 1.15-1.82 (m, 52H), 0.79-1.04 (t, 6H).

(765) Polymer GluN3C16

(766) .sup.1HNMR (500 MHz, CDCl3): 8.04 (s, 1H), 3.20-4.09 (m, 11H), 2.13-3.00 (m, 18H), 1.17-1.51 (m, 78H), 0.81-0.95 (t, 9H).

Example 2. Biological Assays of the Polymers Materials

(767) Cholesterol was purchased from Sigma Aldrich; DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and mPEG2000-DMG (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000](ammonium salt)) were purchased from Avanti Polar Lipids. Slide-A-Lyzer dialysis cassettes were obtained from Pierce Thermo Scientific. The microfluidics devices were made as previously published..sup.22 The RiboGreen was ordered from Invitrogen Life Technologies, and used as according to the manufacturer guidelines. The EPO and luciferase mRNA used were generously provided by Shire. Serum separator tubes were purchased from BD biosciences. The EPO ELISA kits were from R&D Systems Inc.

(768) General Procedures for Synthesis of Polymer Brush Materials.

(769) Poly(glycoamidoamine) (PGAA) was synthesized according to synthetic methods reported by Reineke..sup.11 Polymer structures were confirmed with .sup.1HNMR. PGAAs undergo ring opening reactions with diverse epoxides to afford the desired polymer brush materials. A mixture of PGAA and epoxides (a ratio of 1.5:1 epoxides/amine) in EtOH was irradiated in a microwave oven at 140 C. for 5 h. The reaction mixture was purified by flash chromatography using a solvent system CH.sub.2Cl.sub.2:MeOH:NH.sub.4OH (aqueous) 87.5:11:1.5.

(770) Formulation Procedure

(771) Liposomes were formed using a microfluidics devices, as previously described..sup.22 Briefly, the polymer brush, DOPE, cholesterol, and mPEG2000-DMG were dissolved in ethanol and combined in a 5:2:2:1 weight ratio. The mRNA was dissolved in a 10 mM citrate buffer, pH3.0. The polymer:mRNA weight ratio was 10:1. The ethanol and aqueous solutions were combined in a 1:1 ratio using the microfluidics device, and immediately diluted two-fold in PBS. Formulations were then dialyzed against PBS dialysis cassettes. The relative mRNA entrapment was determined using a RIBOGREEN fluorescent assay and the particle size (e.g., volume mean particle diameter) was determined via dynamic light scattering (ZETAPALS, Brookhaven Instruments).

(772) Cryo-Transmission Electron Microscopy (Cryo-TEM)

(773) Cryo-TEM samples are prepared in a controlled environment vitrification system (CEVS) or using the commercial environmentally controlled automated VITROBOT (FEI, Netherlands), always at a controlled temperature (25 C.) and at saturation. A 6 l drop of the suspension is placed on a 400-mesh TEM copper grid covered with a perforated carbon film. To remove excess solution and produce a thin liquid film the drop is blottedmanually in the CEVS and automatically in the VITROBOT. The blotted sample is then plunged into liquid ethane (183 C.) to form a vitrified specimen and transferred to liquid nitrogen (196 C.) for storage. Vitrified specimens are examined at temperatures below 175 C. using a GATAN 626 cryo holder either in a TECNAI T12 G2 TEM (FEI, Netherlands) or a PHILIPS CM120 TEM operating at 120 kV. Images are recorded on a GATAN MULTISCAN 791 camera or GATAN ULTRASCAN 1000 using the DIGITALMICROGRAPH software (Gatan, U.K.) in the low-dose imaging mode to minimize beam exposure and electron-beam radiation damage, as described..sup.26, 31

(774) Preparation of FFL and Human EPO Messenger RNA

(775) Firefly Luciferase (FFL) and human erythropoietin (hEPO) messenger RNA were synthesized via in vitro transcription from a plasmid DNA template encoding the respective gene. The subsequent transcript was further reacted by the enzymatic addition of a 5 cap structure (Cap 1) and a 3 poly (A) tail of approximately 300 nucleotides in length as determined by gel electrophoresis..sup.32 The messenger RNA was purified using commercially available silica-based spin column technology.

(776) In Vivo EPO mRNA Delivery in Mice

(777) All procedures used in animal studies conducted at MIT were approved by the Institutional Animal Care and Use Committee (IACUC) and were also consistent with local, state and federal regulations as applicable. Formulated mRNA was administered intravenously via tail vein injection using C57BL/6 mice (Charles River Labs, 6 to 8 weeks old, 18-22 grams) were for mRNA expression experiments. After 6 hours, blood was collected from the mice via the tail vein, and serum was obtained using serum separation tubes. EPO levels were measured by an ELISA assay using standard EPO protein.

(778) Biodistribution of TarN3C10-mRNA Nanoparticles in Mice

(779) C57BL/6 mice were administered intravenously via tail vein injection for luciferase mRNA expression experiments. The mice were sacrificed 24 hours post injection; the pancreas, spleen, liver, kidneys, ovaries/uterus, heart, lungs, and thymus as well as a section of the adipose tissue and muscle tissue were then dissected. The tissues were examined with an IVIS imaging system from Caliper. Signal strength of the individual tissue was normalized against tissue weight.

(780) Toxicity Study in Mice

(781) C57Bl/6 mice were administered intravenously TarN3C10 nanoparticles via tail vein injection. Blood and tissue samples were collected 24 and 48 hours after injection from the animals. Histopathology on liver, spleen, kidneys, heart, and lungs were processed and evaluated by the histology core facility of Koch Institute. Immunoassays were used to measure the levels of cytokines in a 96-well plate using BIO-PLEX PRO assays formatted on magnetic beads. 30 different cytokines were analyzed: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17, Exotaxin, G-CSF, GM-CSF, IFN-, KC, MCP-1, MIP-1a, MIP-1b, RANTES, TNG-, IL-18, FGF-basic, LIF, M-CSF, MIG, MIP-2, PDGF-bb, and VEGF. Clinical chemistry of ALT, AST, and total bilirubin were measured by IDEXX Laboratories. Exemplary results are shown in FIGS. 4 and 6 and Table 12.

(782) TABLE-US-00012 TABLE 12 Liver chemistry for TarN3C10-treated mice Time ALT AST TBILI Treatment (hour) (U/L) (U/L) (mg/dL) PBS 24 39.6 6.4 198.2 75.8 0.2 0.1 TarN3C10 24 44.8 3.5 323.5 93.2 0.2 0.0 TarN3C10 48 38.4 3.4 227 55.6 0.2 0.0
Blood samples were taken at 24 & 48 h after administration. Control: PBS. ALT: alanine aminotransferase. AST: aspartate aminotransferase. TBILI: total bilirubin (n=4 or 5).
In Vivo Factor VII (FVII) Silencing in Mice

(783) All procedures used in animal studies conducted at MIT were approved by the Institutional Animal Care and Use Committee (IACUC) and were also consistent with local, state and federal regulations as applicable. PBS (phosphate buffered saline) solutions containing Factor VII siRNA and a polymer described herein were administered to C57BL/6 mice (Charles River Labs, 6 to 8 weeks old, 18-22 grams) at 10 l or 0.03 g per gram of mouse body weight intravenously via tail vein injection for siRNA silencing experiments. After 24 or 48 h, the mice were anaesthetized by isofluorane inhalation for blood sample collection by retroorbital eye bleed using serum separation tubes (Falcon tubes, Becton Dickinson). Protein levels of Factor VII were calculated by chromogenic assay (Biophen FVII, Aniara Corporation) with a standard curve obtained from control mice. Exemplary results are shown in FIGS. 1A to 1C. FVII expression levels were significantly reduced by the polymers.

(784) Exemplary Results

(785) To formulate polymer-mRNA nanoparticles, we first mixed polymers with mRNA without adding additional components. For example, the particle size of TarN3C12-mRNA and GalN3C12-mRNA is 647 and 536 nm, respectively (Table 13). Their PDI is 0.43 and 0.83. In order reduce particle size and improve polydispersity, we incorporated additional formulation components based on our research experience in siRNA delivery..sup.20 The polymer brush materials were subsequently formulated into nanoparticles through combination with cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine)/or DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), mPEG2000-DMG (1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]), and mRNA using a microfluidic based mixing device..sup.22 To evaluate the delivery efficiency of these polymer-brush nanoparticles, mRNA for human erythropoietin (EPO) was incorporated into the formulations. EPO functions to regulate red blood cell production,.sup.7 and is used therapeutically by patients with anemia and myelodysplasia..sup.23 Preliminary study indicated that TarN3C10 formulated with DOPE showed higher expression of EPO than that formulated with DSPC (FIG. 5). Therefore, we formulated all other polymers using DOPE. Characterization of the formulated nanoparticles by dynamic light scattering revealed particle sizes ranging from 56 to 96 nm (Table 13). All formulations produced fine nanoparticles with polydispersity index (PDI) between 0.11-0.27. Additionally, the mRNA loading efficiency, measured using the RiboGreen assay,.sup.17 was as high as 81% for these formulations. Polymer-brush nanoparticles were administered intravenously via tail vein in mice (EPO mRNA dose=0.3 mg/kg) with free mRNA as a control. According to the literature, protein expression with mRNA delivery normally peaks around five to seven hours..sup.4 Six hours following injection, blood was collected and EPO levels were measured by ELISA, with several polymer-brush nanoparticles demonstrating efficacy in delivery of functional EPO mRNA (FIG. 3A).

(786) TABLE-US-00013 TABLE 13 Particle size, polydispersity index (PDI), and percentage of mRNA entrapment. Polymer Particle size (nm) PDI mRNA entrapment % TarN1C10 67 0.16 60 TarN2C10 70 0.16 69 TarN3C10 73 0.14 67 TarN1C12 71* 0.23 76 TarN2C12 57* 0.22 81 TarN3C12 68* 0.18 74 TarN3C12 647 0.43 2 (without other formulation components) TarN1C14 66 0.20 67 TarN2C14 69 0.21 67 TarN3C14 60* 0.23 68 TarN1C16 65* 0.17 70 TarN2C16 64 0.19 66 TarN3C16 63* 0.19 63 GalN2C10 74 0.15 35 GalN3C10 96 0.14 39 GalN2C12 74 0.13 16 GalN3C12 68 0.15 6 GalN3C12 536 0.83 7 (without other formulation components) GalN2C14 94 0.11 15 GalN3C14 93 0.22 14 GalN2C16 97 0.28 34 GalN3C16 84 0.24 22 GluN2C10 76 0.12 32 GluN3C10 56 0.17 24 GluN1C12 77 0.15 17 GluN2C12 75 0.13 19 GluN3C12 91 0.22 14 GluN1C14 82* 0.27 38 GluN2C14 91 0.14 38 GluN3C14 85 0.12 26 GluN1C16 85 0.16 53 GluN2C16 90 0.13 27 GluN3C16 85 0.11 35 *More than one peak.

(787) Analyzing the results from the screen demonstrates that members of the polymer building blocks were able to facilitate some amount of mRNA delivery. If the sugar unit

(788) ##STR00445##
such as glycoamido moieties

(789) ##STR00446##
and alkyl tails are kept constant, efficiency is increased as the number of amino groups is increased (N1<N2<N3; e.g. TarN1C10 vs TarN2C10 vs TarN3C10; GalN2C10 vs GalN3C10; GluN2C10 vs GluN3C10). When comparing the significance of sugar, the tartarate (Tar) series was more efficient than either the galactarate (Gal) or glucarate (Glu) series (e.g. TarN2C10 vs GalN2C10 vs GluN2C10; TarN3C10 vs GalN3C10 vs TarN3C10). The galactarate series demonstrated similar or better efficiency when compared to the glucarate series (e.g. GalN2C10 vs GluN2C10; GalN3C10 vs TarN3C10). Taken together, these results indicate that the number of hydroxyl groups may be important to delivery efficiency. When comparing the polymers described herein on the basis of alkyl tail length, in general, polymers with shorter tails showed better efficiency than those with longer tails (C10>C12>C14>C16, e.g. TarN1C10 vs TarN1C12 vs TarN1C14 vs TarN1C16; TarN2C10 vs TarN2C12 vs TarN2C14 vs TarN2C16; TarN3C10 vs TarN3C12 vs TarN3C14 vs TarN3C16). All together (under current formulation methods), these results suggest guidelines for structure-activity relationships: (1) efficiency is increased as then number of amino groups is increased (N3>N2>N1); (2) the tartarate sugar improves efficiency relative to the galactarate or glucarate sugar; and/or (3) shorter alkyl tails improve efficiency (C10>C12>C14>C16). TarN3C10 was found to be one of the best-performing polymers. TarN3C10 induced EPO expression that resulted in serum EPO concentrations of 1080 ng/mL at a dose of 0.3 mg/kg. This was over one thousand-fold higher than expression following delivery of free EPO mRNA. To our knowledge, this is one of the most efficient mRNA intravenous delivery systems.

(790) We next evaluated the biodistribution by formulating TarN3C10 with luciferase mRNA. In these studies, TarN3C10 nanoparticles were injected intravenously at an mRNA dose of 1 mg/kg. Through luminescence imaging, we measured signal arising from the pancreas, liver, spleen, kidneys, uterus/ovaries, fat, muscle, lungs, heart, and thymus (FIG. 3B). Luciferase expression following mRNA delivery with TarN3C10 nanoparticles was over one thousand fold higher in the liver and spleen compared to the administration of free mRNA, normalized by tissue weight. Additionally, over ten-fold higher luciferase expression was detected in the pancreas, uterus/ovaries, fat, kidneys, muscle, lungs, heart, and thymus for TarN3C10-treated animals relative to the free mRNA control.

(791) TarN3C10 nanoparticles were further characterized using cryogenic transmission electron microscopy..sup.24-26 Without mRNA (FIG. 3C), the TarN3C10 nanoparticles form round spherical particles. The addition of mRNA (FIGS. 3D and 3E) results in the formation of more complex structures. It is proposed that TarN3C10 and other formulation components may compose the core of the observed structures, surrounded by internally ordered domains. At higher magnification, the nanoparticles demonstrated multiple envelope domains (FIG. 3E, arrow)..sup.27, 28

CONCLUSION

(792) We have described the synthesis and evaluation of novel polymer-brush nanoparticles for efficient mRNA delivery. A modular design strategy enabled the creation of polymers with building blocks consisting of amino groups, multiple hydroxyl groups, and alkyl tails. Analyzing structure-activity relationships indicates that all three building blocks contribute to efficient mRNA encapsulation and delivery. The key structural features of top performing revealed that more amino groups may be favorable, the tartarate series may be more potent than the galactarate or glucarate series, and alkyl tails may improve performance. These guidelines can be used to inform the design of next-generation mRNA delivery systems. Our study indicated that polymer/mRNA polyplex formed particles with larger size and higher polydispersity index in comparison to formulations with DOPE, cholesterol, and PEG-DMG. We note that humans with chemotherapy-related anemia receive EPO at 40,000 units/week, translating to approximately 308 g..sup.30 TarN3C10 induced EPO expression of 1080 ng/mL with an mRNA dose of 0.3 mg/kg. This would translate to a dose roughly 10-fold higher than that used clinically for EPO. Finally, a single dose toxicity study revealed TarN3C10 nanoparticles are well tolerated based on histopathology, broad panel cytokine screening, and liver blood chemistry profiles. As such, strategies based on the platform of polymer-brush nanoparticles reported here may have promise for use in mRNA-based therapy.

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EQUIVALENTS AND SCOPE

(794) In the claims articles such as a, an, and the may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include or between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

(795) Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms comprising and containing are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

(796) This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

(797) Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.