Polyamine-fatty acid derived lipidoids and uses thereof

Abstract

The present disclosure provides polyamine-fatty acid derived lipidoids (e.g., compounds of Formula (I) or (II)) and methods of preparing the lipidoids. A described lipidoid includes R—C(═O)—O— moieties (where R is a lipid moiety), which may be hydrolyzed into non-toxic fatty acids. Also provided are compositions including a described lipidoid and an agent (e.g., polynucleotide, small molecule, peptide, or protein). The present disclosure also provides methods, kits, and uses that involve the lipidoids or compositions for delivering an agent to a subject, tissue, or cell and/or for treating and/or preventing a range of diseases, such as genetic diseases, proliferative diseases, hematological diseases, neurological diseases, immunological diseases, gastrointestinal diseases, respiratory diseases, painful conditions, psychiatric disorders, and metabolic disorders. ##STR00001##

Claims

1. A compound of Formula (I): ##STR00327## or a salt thereof, wherein: X is of the formula: ##STR00328## wherein: each instance of p is independently 1, 2, 3, 4, 5, or 6; and each instance of R.sup.N is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; L.sup.1a is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; R.sup.A1a is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl; R.sup.B1 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a nitrogen protecting group, or a moiety of the formula: ##STR00329## wherein L.sup.1b is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, and R.sup.A1b is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl; L.sup.2a is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; R.sup.A2a is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl; and R.sup.B2 is hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, a nitrogen protecting group, or a moiety of the formula: ##STR00330## wherein L.sup.2b is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, and R.sup.A2b is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl.

2. The compound of claim 1, wherein the compound is of Formula (I-B): ##STR00331## or a salt thereof.

3. The compound of claim 1, wherein each of L.sup.1a and L.sup.2a is independently substituted or unsubstituted alkylene; or a salt thereof.

4. The compound of claim 2, wherein each of L.sup.1a, L.sup.a2, L.sup.1b, and L.sup.2b is independently substituted or unsubstituted alkylene; or a salt thereof.

5. The compound of claim 1, wherein at least one of R.sup.A1a and R.sup.A2a is substituted or unsubstituted, C.sub.7-24 alkyl, or substituted or unsubstituted, C.sub.7-24 alkenyl; or a salt thereof.

6. The compound of claim 1, wherein each one of R.sup.B1 and R.sup.B2 is independently hydrogen or substituted or unsubstituted alkyl; or a salt thereof.

7. The compound of claim 1, wherein the compound is of the formula: ##STR00332## or a salt thereof.

8. The compound of claim 1, wherein the compound is of formula: ##STR00333## ##STR00334## ##STR00335## or a salt thereof.

9. A particle comprising: a compound of claim 1, or a salt thereof; and an agent.

10. A composition comprising a compound of claim 1, or a salt thereof, and optionally an excipient.

11. A composition comprising a particle of claim 9, and optionally an excipient.

12. A method of delivering an agent to a subject, the method comprising administering to the subject a composition of claim 10, wherein the composition further comprises an agent.

13. A method of delivering an agent to a cell, the method comprising contacting the cell with a composition of claim 10, wherein the composition further comprises an agent.

14. The compound of claim 1, wherein X is of the formula: ##STR00336## or a salt thereof.

15. The compound of claim 1, wherein the compound is of Formula (I-C): ##STR00337## or a salt thereof, wherein each instance oft is 2, 3, 4, 5, or 6.

16. The compound of claim 1, wherein the compound is of the formula: ##STR00338## or a salt thereof, wherein each instance oft is 2, 3, 4, 5, or 6.

17. The compound of claim 2, wherein each of R.sup.A1a, R.sup.A2a, R.sup.A1b, and R.sup.A2b is independently unsubstituted C.sub.7-24 alkyl or unsubstituted C.sub.7-24 alkenyl; or a salt thereof.

18. The compound of claim 2, wherein each of R.sup.A1a, R.sup.A2a, R.sup.A1b, and R.sup.A2b is independently: C.sub.7-24 alkyl substituted with one or more instances of halogen; or C.sub.7-24 alkenyl substituted with one or more instances of halogen; or a salt thereof.

19. The compound of claim 1, wherein the compound is of Formula (I-A): ##STR00339## or a salt thereof.

20. The compound of claim 19, wherein each of L.sup.1a, L.sup.2a, and L.sup.1b is independently substituted or unsubstituted alkylene; or a salt thereof.

21. The compound of claim 1, wherein the compound is of Formula (I-H): ##STR00340## or a salt thereof, wherein each instance oft is 2, 3, 4, 5, or 6.

22. The compound of claim 19, wherein each one of R.sup.A1a, R.sup.A2a, and R.sup.A1b is independently unsubstituted C.sub.7-24 alkyl or unsubstituted C.sub.7-24 alkenyl; or a salt thereof.

23. The compound of claim 19, wherein each one of R.sup.A1a, R.sup.A2a, and R.sup.A1b is independently: C.sub.7-24 alkyl substituted with one or more instances of halogen; or C.sub.7-24 alkenyl substituted with one or more instances of halogen; or a salt thereof.

24. The compound of claim 1, wherein the compound is of the formula: ##STR00341## or a salt thereof.

25. The composition of claim 10 further comprising an agent.

26. The composition of claim 25, wherein the agent is a small molecule, protein, peptide, or polynucleotide.

27. The composition of claim 25, wherein the agent is a DNA or RNA.

28. The composition of claim 25, wherein the agent is a small interfering RNA (siRNA) or messenger RNA (mRNA).

29. The composition of claim 25, wherein the agent is a 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) FIG. 1 shows that compound 24C18Oleic exhibited splenic luciferase mRNA expression at 6 hours.

(2) FIG. 2 shows exemplary erythropoietin (EPO) serum levels at 6 hours after a 1 mg/kg injection of a composition that includes EPO mRNA and compound 24C18Oleic, 24C18Linoleic2, or 24C18Linoleic3.

(3) FIG. 3 shows exemplary HeLa cell luminescence results at 24 hours after treating HeLa cells with 10 ng of a composition that includes luciferase mRNA and an exemplary compound of the disclosure.

(4) FIGS. 4A to 4C show exemplary proton nuclear magnetic resonance (CDCl.sub.3) spectra of compounds 24C18Oleic (FIG. 4A), 24C18Linoleic3 (FIG. 4B), and 50C18Linoleic3 (FIG. 4C).

(5) FIGS. 5A to 5P show exemplary proton nuclear magnetic resonance spectra of compounds (A) 50-C2-CC-DD core, (B) 50-C3-CC-DD core, (C) 50-C4-CC-DD core, (D) 50-C5-CC-DD core, (E) 50-C2-C9-4tail, (F) 50-C2-C12-4tail, (G) 50-C2-C15-4tail, (H) 50-C2-C18oleic-4tail, (I) 50-C2-C18elaidic-4tail, (J) 50-C2-C18lin2-4tail, (K) 50-C3-C18lin2-4tail, (L) 50-C4-C7-4tail, (M) 50-C4-C10-4tail, (N) 50-C4-C13-4tail, (0) 50-C4-C18oleic-4tail, and (P) 50-C4-C18lin2-4tail.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

(6) The present disclosure provides compounds and uses thereof. In one aspect, described herein are compounds of Formula (I) or (II). Also described herein are compositions including a compound described herein and optionally an excipient. In certain embodiments, the compositions further include an agent (e.g., a polynucleotide (e.g., an RNA or DNA), small molecule, peptide, or protein). The compounds and compositions have been found to be able to deliver effectively and efficiently an agent to a subject, tissue, or cell. A compound of the disclosure, which includes one or more amino moieties that may be protonated to form positively charged ammonium cation(s), may bind to an agent that includes negatively charged moieties to form a complex. A compound described herein also includes one or more lipid moieties (e.g., substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl). The lipid moieties are typically hydrophobic and may assist the compound and/or a complex of the compound and the agent to pass through cell membranes and/or mask the charge on the agent to be delivered. A described compound includes R—C(═O)—O— moieties (where R is a lipid moiety), which may be hydrolyzed into non-toxic carboxylic acids (e.g., fatty acids). Therefore, the compounds described herein may be biodegradable and/or non-toxic. In certain embodiments, a composition described herein that includes a plurality of molecules of a compound of the disclosure is in the form of particles. An agent may be encapsulated within or otherwise associated with the particles. 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, immunological diseases, gastrointestinal diseases (e.g., liver diseases), spleen diseases, respiratory diseases (e.g., lung diseases)), painful conditions, psychiatric disorders, and metabolic disorders in a subject in need thereof.

(7) Compounds

(8) In one aspect, the present disclosure provides compounds of Formula (I):

(9) ##STR00013##
and salts, hydrates, solvates, polymorphs, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(10) X is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted heteroalkenylene, substituted or unsubstituted heteroalkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, a divalent moiety of the formula:

(11) ##STR00014##
or a combination thereof, wherein each instance of R.sup.X 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, a nitrogen protecting group, or a moiety of the formula:

(12) ##STR00015##
or R.sup.B1 and an instance of R.sup.X are joined to form a substituted or unsubstituted, heterocyclic ring or a substituted or unsubstituted, heteroaryl ring, or R.sup.B2 and an instance of R.sup.X are joined to form a substituted or unsubstituted, heterocyclic ring or a substituted or unsubstituted, heteroaryl ring, wherein: each instance of L.sup.X is independently substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene; and each instance of R.sup.X1 is independently substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl;

(13) L.sup.1a is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;

(14) R.sup.A1a is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl;

(15) R.sup.B1 is 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, or a moiety of the formula:

(16) ##STR00016##
wherein L.sup.1b is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, and R.sup.A1b is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl;

(17) L.sup.2a is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene;

(18) R.sup.A2a is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl; and

(19) R.sup.B2 is 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, or a moiety of the formula:

(20) ##STR00017##
wherein L.sup.2b is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, and R.sup.A2b is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl;

(21) or R.sup.B1 and R.sup.B2 are joined to form a substituted or unsubstituted, heterocyclic ring or a substituted or unsubstituted, heteroaryl ring.

(22) Formula (I) includes a divalent moiety X. In certain embodiments, X comprises substituted alkylene. In certain embodiments, X comprises a moiety shown in Table 2. In certain embodiments, X comprises unsubstituted alkylene. In certain embodiments, X comprises a moiety shown in Table 1. In certain embodiments, X comprises substituted C.sub.1-6 alkylene. In certain embodiments, X comprises C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, X comprises C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, X comprises C.sub.1-6 perfluoroalkylene. In certain embodiments, X comprises unsubstituted C.sub.1-6 alkylene. In certain embodiments, X comprises

(23) ##STR00018##
In certain embodiments, X comprises

(24) ##STR00019##
In certain embodiments, X comprises

(25) ##STR00020##
In certain embodiments, X comprises

(26) ##STR00021##
and/or

(27) ##STR00022##
In certain embodiments, X is of the formula:

(28) ##STR00023##
In certain embodiments, X is of the formula:

(29) ##STR00024##
In certain embodiments, X is of the formula

(30) ##STR00025##
In certain embodiments, X is of the formula:

(31) ##STR00026##
In certain embodiments, X is a moiety shown in Table 1. In certain embodiments, X is a moiety shown in Table 2.

(32) TABLE-US-00001 TABLE 1 Exemplary unsubstituted alkylene moieties embedded image 0 0

(33) TABLE-US-00002 TABLE 2 Exemplary substituted alkylene moieties embedded image 0 0

(34) In certain embodiments, X comprises substituted alkenylene. In certain embodiments, X comprises unsubstituted alkenylene. In certain embodiments, X comprises substituted C.sub.1-6 alkenylene. In certain embodiments, X comprises C.sub.2-6 alkenylene substituted with at least one halogen. In certain embodiments, X comprises C.sub.2-6 alkenylene substituted with at least one fluorine. In certain embodiments, X comprises C.sub.2-6 perfluoroalkenylene. In certain embodiments, X comprises unsubstituted C.sub.2-6 alkenylene. In certain embodiments, X comprises unsubstituted vinylene. In certain embodiments, X comprises unsubstituted propenylene. In certain embodiments, X comprises unsubstituted butenylene. In certain embodiments, X comprises unsubstituted pentenylene. In certain embodiments, X comprises unsubstituted hexenylene. In certain embodiments, X is unsubstituted vinylene. In certain embodiments, X is unsubstituted propenylene. In certain embodiments, X is unsubstituted butenylene. In certain embodiments, X is unsubstituted pentenylene. In certain embodiments, X is unsubstituted hexenylene.

(35) In certain embodiments, X comprises substituted alkynylene. In certain embodiments, X comprises unsubstituted alkynylene. In certain embodiments, X comprises substituted C.sub.1-6 alkynylene. In certain embodiments, X comprises C.sub.2-6 alkynylene substituted with at least one halogen. In certain embodiments, X comprises C.sub.2-6 alkynylene substituted with at least one fluorine. In certain embodiments, X comprises C.sub.2-6 perfluoroalkynylene. In certain embodiments, X comprises unsubstituted C.sub.2-6 alkynylene. In certain embodiments, X comprises —C≡C—. In certain embodiments, X comprises unsubstituted propynylene. In certain embodiments, X comprises unsubstituted butynylene. In certain embodiments, X comprises unsubstituted pentynylene. In certain embodiments, X comprises unsubstituted hexynylene. In certain embodiments, X is —C≡C—. In certain embodiments, X is unsubstituted propynylene. In certain embodiments, X is unsubstituted butynylene. In certain embodiments, X is unsubstituted pentynylene. In certain embodiments, X is unsubstituted hexynylene.

(36) In certain embodiments, X comprises substituted heteroalkylene. In certain embodiments, X comprises unsubstituted heteroalkylene. In certain embodiments, X comprises is a moiety shown in Table 3. In certain embodiments, a heteroalkylene moiety consists of one, two, three, or four heteroatoms in the heteroalkylene chain, wherein the heteroatoms are independently selected from the group consisting of nitrogen, oxygen, or sulfur. In certain embodiments, X comprises substituted C.sub.1-6 heteroalkylene. In certain embodiments, X comprises C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, X comprises C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, X comprises unsubstituted C.sub.1-6 heteroalkylene. In certain embodiments, X is unsubstituted C.sub.1-6 heteroalkylene. In certain embodiments, X is a moiety shown in Table 3.

(37) TABLE-US-00003 TABLE 3 Exemplary unsubstituted heteroalkylene moieties (wherein each instance of R.sup.X is independently unsubstituted C.sub.1-6 alkyl) embedded image 0

(38) In certain embodiments, X comprises substituted heteroalkenylene. In certain embodiments, X comprises unsubstituted heteroalkenylene. In certain embodiments, a heteroalkenylene moiety consists of one, two, three, or four heteroatoms in the heteroalkenylene chain, wherein the heteroatoms are independently selected from the group consisting of nitrogen, oxygen, or sulfur. In certain embodiments, X comprises substituted C.sub.1-6 heteroalkenylene. In certain embodiments, X comprises C.sub.1-6 heteroalkenylene substituted with at least one halogen. In certain embodiments, X comprises C.sub.1-6 heteroalkenylene substituted with at least one fluorine. In certain embodiments, X comprises unsubstituted C.sub.1-6 heteroalkenylene. In certain embodiments, X is unsubstituted C.sub.1-6 heteroalkenylene.

(39) In certain embodiments, X comprises substituted heteroalkynylene. In certain embodiments, X comprises unsubstituted heteroalkynylene. In certain embodiments, a heteroalkynylene moiety consists of one, two, three, or four heteroatoms in the heteroalkynylene chain, wherein the heteroatoms are independently selected from the group consisting of nitrogen, oxygen, or sulfur. In certain embodiments, X comprises substituted C.sub.1-6 heteroalkynylene. In certain embodiments, X comprises C.sub.1-6 heteroalkynylene substituted with at least one halogen. In certain embodiments, X comprises C.sub.1-6 heteroalkynylene substituted with at least one fluorine. In certain embodiments, X comprises unsubstituted C.sub.1-6 heteroalkynylene. In certain embodiments, X is unsubstituted C.sub.1-6 heteroalkynylene.

(40) In certain embodiments, X comprises substituted carbocyclylene. In certain embodiments, X comprises unsubstituted carbocyclylene. In certain embodiments, X comprises saturated carbocyclylene. In certain embodiments, X comprises unsaturated carbocyclylene. In certain embodiments, X comprises monocyclic carbocyclylene. In certain embodiments, X comprises 3- to 7-membered, monocyclic carbocyclylene.

(41) In certain embodiments, X comprises substituted heterocyclylene. In certain embodiments, X comprises unsubstituted heterocyclylene. In certain embodiments, X comprises saturated heterocyclylene. In certain embodiments, X comprises unsaturated heterocyclylene. In certain embodiments, X comprises substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclylene, wherein one, two, or three atoms in the heterocyclylene ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, X comprises substituted or unsubstituted, 6-membered monocyclic heterocyclylene, wherein one or two atoms in the heterocyclylene ring system are independently nitrogen, oxygen, or sulfur. In certain embodiments, X comprises a divalent moiety of the formula:

(42) ##STR00079##
wherein the divalent moiety is substituted (e.g., substituted with one or more halogen, substituted or unsubstituted C.sub.1-6 alkyl, and/or oxo) or unsubstituted. In certain embodiments, X comprises a divalent moiety of the formula:

(43) ##STR00080##
In certain embodiments, X comprises a divalent moiety of the formula:

(44) ##STR00081##
wherein the divalent moiety is substituted (e.g., with one or more halogen) or unsubstituted. In certain embodiments, X comprises a divalent moiety of the formula:

(45) ##STR00082##
wherein the divalent moiety is substituted (e.g., substituted with one or more halogen, substituted or unsubstituted C.sub.1-6 alkyl, and/or oxo) or unsubstituted. In certain embodiments, X comprises a divalent moiety of the formula:

(46) ##STR00083##
In certain embodiments, X comprises a divalent moiety of the formula:

(47) ##STR00084##
In certain embodiments, X comprises a divalent moiety of the formula:

(48) ##STR00085##

(49) In certain embodiments, all instances of R.sup.N are the same. In certain embodiments, two instances of R.sup.N are different from each other. In certain embodiments, at least one instance of R.sup.N is hydrogen. In certain embodiments, each instance of R.sup.N is hydrogen. In certain embodiments, at least one instance of R.sup.N is substituted or unsubstituted C.sub.1-6 alkyl (e.g., —CH.sub.3, —CF.sub.3, unsubstituted ethyl, perfluoroethyl, unsubstituted propyl, perfluoropropyl, unsubstituted butyl, or perfluorobutyl). In certain embodiments, at least one instance of R.sup.N is a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

(50) In certain embodiments, X comprises substituted arylene. In certain embodiments, X comprises unsubstituted arylene. In certain embodiments, X comprises 6- to 10-membered arylene. In certain embodiments, X comprises substituted phenylene. In certain embodiments, X comprises unsubstituted phenylene. In certain embodiments, X comprises substituted heteroarylene. In certain embodiments, X comprises unsubstituted heteroarylene. In certain embodiments, X comprises heteroarylene, wherein one, two, three, or four atoms in the heteroarylene ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, X comprises monocyclic heteroarylene. In certain embodiments, X comprises 5-membered, monocyclic heteroarylene. In certain embodiments, X comprises 6-membered, monocyclic heteroarylene. In certain embodiments, X comprises bicyclic heteroarylene, wherein the point of attachment may be on any atom of the bicyclic heteroarylene ring system, as valency permits. In certain embodiments, X comprises 9- or 10-membered, bicyclic heteroarylene.

(51) In certain embodiments, X comprises a divalent moiety of the formula:

(52) ##STR00086##
In certain embodiments, X comprises a divalent moiety of the formula:

(53) ##STR00087##

(54) In certain embodiments, all instances of R.sup.X are the same. In certain embodiments, two instances of R.sup.X are different from each other. In certain embodiments, at least one instance of R.sup.X is H. In certain embodiments, at least one instance of R.sup.X is substituted acyl. In certain embodiments, at least one instance of R.sup.X is unsubstituted acyl. In certain embodiments, at least one instance of R.sup.X is acetyl. In certain embodiments, at least one instance of R.sup.X is substituted alkyl. In certain embodiments, at least one instance of R.sup.X is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.X is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.X is methyl. In certain embodiments, at least one instance of R.sup.X is ethyl. In certain embodiments, at least one instance of R.sup.X is propyl. In certain embodiments, at least one instance of R.sup.X is butyl. In certain embodiments, at least one instance of R.sup.X is pentyl. In certain embodiments, at least one instance of R.sup.X is hexyl. In certain embodiments, at least one instance of R.sup.X is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.X is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.X is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.X is 3 to 7 membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.X is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.X is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.X is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.X is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.X is 3 to 7 membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.X is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.X is 6 to 10 membered aryl. In certain embodiments, at least one instance of R.sup.X is monocyclic aryl. In certain embodiments, at least one instance of R.sup.X is substituted phenyl. In certain embodiments, at least one instance of R.sup.X is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.X is bicyclic aryl. In certain embodiments, at least one instance of R.sup.X is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.X is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.X is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.X is 5 or 6 membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.X 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 R.sup.X is a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.X is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. In certain embodiments, at least one instance of R.sup.X is a moiety of the formula:

(55) ##STR00088##
In certain embodiments, R.sup.B1 and an instance of R.sup.X are joined to form a substituted or unsubstituted, heterocyclic ring. In certain embodiments, R.sup.B1 and an instance of R.sup.X are joined to form a 3- to 7-membered, monocyclic heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B1 and an instance of R.sup.X are joined to form a substituted or unsubstituted, heteroaryl ring. In certain embodiments, R.sup.B1 and an instance of R.sup.X are joined to form a 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, or three atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B1 and an instance of R.sup.X are joined to form a 9- to 10-membered, bicyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B2 and an instance of R.sup.X are joined to form a substituted or unsubstituted, heterocyclic ring. In certain embodiments, R.sup.B2 and an instance of R.sup.X are joined to form a 3- to 7-membered, monocyclic heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B2 and an instance of R.sup.X are joined to form a substituted or unsubstituted, heteroaryl ring. In certain embodiments, R.sup.B2 and an instance of R.sup.X are joined to form a 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, or three atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B2 and an instance of R.sup.X are joined to form a 9- to 10-membered, bicyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur.

(56) In certain embodiments, all instances of L.sup.X are the same. In certain embodiments, two instances of L.sup.X are different from each other. In certain embodiments, at least one instance of L.sup.X is substituted alkylene. In certain embodiments, at least one instance of L.sup.X is a moiety shown in Table 2. In certain embodiments, at least one instance of L.sup.X is unsubstituted alkylene. In certain embodiments, at least one instance of L.sup.X is a moiety shown in Table 1. In certain embodiments, at least one instance of L.sup.X is substituted C.sub.1-6 alkylene. In certain embodiments, at least one instance of L.sup.X is C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, at least one instance of L.sup.X is C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, at least one instance of L.sup.X is C.sub.1-6 perfluoroalkylene. In certain embodiments, at least one instance of L.sup.X is unsubstituted C.sub.1-6 alkylene. In certain embodiments, at least one instance of L.sup.X is of the formula:

(57) ##STR00089##
In certain embodiments, at least one instance of L.sup.X is of the formula:

(58) ##STR00090##
In certain embodiments, at least one instance of L.sup.X is of the formula:

(59) ##STR00091##

(60) In certain embodiments, at least one instance of L.sup.X is substituted heteroalkylene. In certain embodiments, at least one instance of L.sup.X is unsubstituted heteroalkylene. In certain embodiments, at least one instance of L.sup.X is a moiety shown in Table 3. In certain embodiments, at least one instance of L.sup.X is substituted C.sub.1-6 heteroalkylene. In certain embodiments, at least one instance of L.sup.X is C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, at least one instance of L.sup.X is C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, at least one instance of L.sup.X is unsubstituted C.sub.1-6 heteroalkylene.

(61) In certain embodiments, all instances of R.sup.X1 are the same. In certain embodiments, two instances of R.sup.X1 are different from each other. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.4-30 alkyl. In certain embodiments, at least one instance of R.sup.X1 is a moiety shown in Table 5. R.sup.X1 is C.sub.4-30 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.4-30 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.X1 is C.sub.4-30 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.4-30 alkyl. In certain embodiments, at least one instance of R.sup.X1 is a moiety shown in Table 4. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.4-30 alkyl. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.7-24 alkyl. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.7-24 alkyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.7-24 alkyl. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.9-19 alkyl. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 alkyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 alkyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 perfluoroalkyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.9-19 alkyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.9-19 alkyl. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.4-30 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is C.sub.4-30 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.4-30 alkenyl substituted with one or more fluorine.

(62) In certain embodiments, at least one instance of R.sup.X1 is C.sub.4-30 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.4-30 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is a moiety shown in Table 6. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.4-30 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.7-24 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.7-24 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.7-24 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.9-19 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 alkenyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 alkenyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 perfluoroalkenyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.9-19 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.9-19 alkenyl. In certain embodiments, at least one instance of R.sup.X1 is alkenyl described herein and includes one, two, three, four, five, or six C═C double bonds. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.4-30 alkynyl. In certain embodiments, at least one instance of R.sup.X1 is C.sub.4-30 alkynyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.4-30 alkynyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.X1 is C.sub.4-30 perfluoroalkynyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.4-30 alkynyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.4-30 alkynyl. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.7-24 alkynyl. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 alkynyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 alkynyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.X1 is C.sub.7-24 perfluoroalkynyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.7-24 alkynyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.7-24 alkynyl. In certain embodiments, at least one instance of R.sup.X1 is substituted C.sub.9-19 alkynyl. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 alkynyl substituted with one or more halogen. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 alkynyl substituted with one or more fluorine. In certain embodiments, at least one instance of R.sup.X1 is C.sub.9-19 perfluoroalkynyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted C.sub.9-19 alkynyl. In certain embodiments, at least one instance of R.sup.X1 is unsubstituted and unbranched C.sub.9-19 alkynyl.

(63) TABLE-US-00004 TABLE 4 Exemplary unsubstituted alkyl moieties embedded image 00 01 02 03 04 05 06 07 08

(64) TABLE-US-00005 TABLE 5 Exemplary substituted alkyl moieties 09 embedded image 0 0

(65) TABLE-US-00006 TABLE 6 Exemplary unsubstituted alkenyl moieties embedded image 0 0 —(CH.sub.2).sub.7CH═CH(CH.sub.2).sub.3CH.sub.3 —(CH.sub.2).sub.7CH═CH(CH.sub.2).sub.5CH.sub.3 —(CH.sub.2).sub.4CH═CH(CH.sub.2).sub.8CH.sub.3 —(CH.sub.2).sub.7CH═CH(CH.sub.2).sub.7CH.sub.3 —(CH.sub.2).sub.7CH═CHCH.sub.2CH═CH(CH.sub.2).sub.4CH.sub.3 —(CH.sub.2).sub.7CH═CHCH.sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH.sub.3 —(CH.sub.2).sub.3CH═CHCH.sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH═CH(CH.sub.2).sub.4CH.sub.3 —(CH.sub.2).sub.3CH═CHCH.sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH.sub.3 —(CH.sub.2).sub.11CH═CH(CH.sub.2).sub.7CH.sub.3 —(CH.sub.2).sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH═CHCH.sub.2CH═CH—CH.sub.2CH.sub.3 embedded image 0

(66) In Formula (I), X may be a combination of two or more divalent moieties described herein. Reference to divalent linker (e.g., X) being a combination of two or more divalent moieties described herein refers to a divalent linker consisting of at least one instance of a first divalent moiety and at least one instance of a second divalent moiety, wherein the first and second divalent moieties are the same or different and are within the scope of the divalent moieties described herein, and the instances of the first and second divalent moieties are consecutive covalently attached to each other. For example, when X is a combination of alkylene and heteroalkylene, divalent linkers -alkylene-alkylene-, -alkylene-heterocyclylene-, -alkylene-(heterocyclylene).sub.2-, and -heterocyclylene-alkylene-heterocyclylene- are all within the scope of X, wherein each instance of alkylene in any one of the divalent linkers may be the same or different, and each instance of heterocyclylene in any one of the divalent linkers may be the same or different. In certain embodiments, X is a combination of one or more substituted or unsubstituted alkylene, one or more substituted or unsubstituted heteroalkylene, and one or more substituted or unsubstituted heterocyclylene. In certain embodiments, X is a combination of one or more substituted or unsubstituted alkylene and one or more substituted or unsubstituted heteroalkylene. In certain embodiments, X is a combination of one or more substituted or unsubstituted alkylene and one or more substituted or unsubstituted heterocyclylene. In certain embodiments, X is a combination of one or more substituted or unsubstituted heteroalkylene and one or more substituted or unsubstituted heterocyclylene. In certain embodiments, X is of the formula:

(67) ##STR00159##
or a combination thereof. In certain embodiments, X is of the formula:

(68) ##STR00160##
In certain embodiments, X is of the formula:

(69) ##STR00161##
Each instance of p is independently 1, 2, 3, 4, 5, or 6. In certain embodiments, all instances of p are the same. In certain embodiments, two instances of p are different from each other. In certain embodiments, each instance of p is 3, 4, or 5 (e.g., 4). In certain embodiments, X is of the formula:

(70) ##STR00162##
In certain embodiments, X is of the formula:

(71) ##STR00163##
Each instance of q is independently 1, 2, 3, 4, 5, or 6. In certain embodiments, all instances of q are the same. In certain embodiments, two instances of q are different from each other. In certain embodiments, each instance of q is 2, 3, or 4 (e.g., 2). The number r is 1, 2, 3, 4, 5, or 6. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. In certain embodiments, r is 4. In certain embodiments, r is 5. In certain embodiments, r is 6.

(72) Formula (I) includes divalent linker L.sup.1a. In certain embodiments, L.sup.1a is substituted alkylene. In certain embodiments, L.sup.1a is a moiety shown in Table 2. In certain embodiments, L.sup.1a is unsubstituted alkylene. In certain embodiments, L.sup.1a is a moiety shown in Table 1. In certain embodiments, L.sup.1a is substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1a is C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, L.sup.1a is C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, L.sup.1a is C.sub.1-6 perfluoroalkylene. In certain embodiments, L.sup.1a is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1a is of the formula:

(73) ##STR00164##
In certain embodiments, L.sup.1a is of the formula:

(74) ##STR00165##
In certain embodiments, L.sup.1a is of the formula:

(75) ##STR00166##

(76) In certain embodiments, L.sup.1a is substituted heteroalkylene. In certain embodiments, L.sup.1a is unsubstituted heteroalkylene. In certain embodiments, L.sup.1a is a moiety shown in Table 3. In certain embodiments, L.sup.1a is substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.1a is C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, L.sup.1a is C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, L.sup.1a is unsubstituted C.sub.1-6 heteroalkylene.

(77) Formula (I) includes substituent R.sup.A1a. In certain embodiments, R.sup.A1a is substituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A1a is a moiety shown in Table 5. In certain embodiments, R.sup.A1a is C.sub.4-30 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.4-30 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.4-30 perfluoroalkyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A1a is a moiety shown in Table 4. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.4-30 alkyl. In certain embodiments, R.sup.A1a is substituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A1a is C.sub.7-24 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.7-24 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.7-24 perfluoroalkyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.7-24 alkyl. In certain embodiments, R.sup.A1a is substituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A1a is C.sub.9-19 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.9-19 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.9-19 perfluoroalkyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.9-19 alkyl.

(78) In certain embodiments, R.sup.A1a is substituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A1a is C.sub.4-30 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.4-30 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.4-30 perfluoroalkenyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A1a is a moiety shown in Table 6. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.4-30 alkenyl. In certain embodiments, R.sup.A1a is substituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A1a is C.sub.7-24 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.7-24 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.7-24 perfluoroalkenyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.7-24 alkenyl. In certain embodiments, R.sup.A1a is substituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A1a is C.sub.9-19 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.9-19 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.9-19 perfluoroalkenyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.9-19 alkenyl. In certain embodiments, R.sup.A1a is alkenyl described herein and includes one, two, three, four, five, or six C═C double bonds.

(79) In certain embodiments, R.sup.A1a is substituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A1a is C.sub.4-30 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.4-30 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.4-30 perfluoroalkynyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.4-30 alkynyl. In certain embodiments, R.sup.A1a is substituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A1a is C.sub.7-24 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.7-24 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.7-24 perfluoroalkynyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.7-24 alkynyl. In certain embodiments, R.sup.A1a is substituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A1a is C.sub.9-19 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A1a is C.sub.9-19 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A1a is C.sub.9-19 perfluoroalkynyl. In certain embodiments, R.sup.A1a is unsubstituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A1a is unsubstituted and unbranched C.sub.9-19 alkynyl.

(80) Formula (I) includes substituent R.sup.B1. In certain embodiments, R.sup.B1 is H. In certain embodiments, R.sup.B1 is substituted acyl. In certain embodiments, R.sup.B1 is unsubstituted acyl. In certain embodiments, R.sup.B1 is acetyl. In certain embodiments, R.sup.B1 is substituted alkyl. In certain embodiments, R.sup.B1 is unsubstituted alkyl. In certain embodiments, R.sup.B1 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B1 is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.B1 is substituted methyl. In certain embodiments, R.sup.B1 is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, R.sup.B1 is —CH.sub.3. In certain embodiments, R.sup.B1 is ethyl. In certain embodiments, R.sup.B1 is propyl. In certain embodiments, R.sup.B1 is butyl. In certain embodiments, R.sup.B1 is pentyl. In certain embodiments, R.sup.B1 is hexyl. In certain embodiments, R.sup.B1 is substituted alkenyl. In certain embodiments, R.sup.B1 is unsubstituted alkenyl. In certain embodiments, R.sup.B1 is substituted C.sub.1-6 alkenyl. In certain embodiments, R.sup.B1 is unsubstituted C.sub.1-6 alkenyl. In certain embodiments, R.sup.B1 is vinyl. In certain embodiments, R.sup.B1 is substituted alkynyl. In certain embodiments, R.sup.B1 is unsubstituted alkynyl.

(81) In certain embodiments, R.sup.B1 is substituted C.sub.1-6 alkynyl. In certain embodiments, R.sup.B1 is unsubstituted C.sub.1-6 alkynyl. In certain embodiments, R.sup.B1 is substituted carbocyclyl. In certain embodiments, R.sup.B1 is unsubstituted carbocyclyl. In certain embodiments, R.sup.B1 is saturated carbocyclyl. In certain embodiments, R.sup.B1 is unsaturated carbocyclyl. In certain embodiments, R.sup.B1 is monocyclic carbocyclyl. In certain embodiments, R.sup.B1 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.B1 is substituted heterocyclyl. In certain embodiments, R.sup.B1 is unsubstituted heterocyclyl. In certain embodiments, R.sup.B1 is saturated heterocyclyl. In certain embodiments, R.sup.B1 is unsaturated heterocyclyl. In certain embodiments, R.sup.B1 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B1 is monocyclic heterocyclyl. In certain embodiments, R.sup.B1 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.B1 is substituted aryl. In certain embodiments, R.sup.B1 is unsubstituted aryl. In certain embodiments, R.sup.B1 is 6- to 10-membered aryl. In certain embodiments, R.sup.B1 is substituted phenyl. In certain embodiments, R.sup.B1 is unsubstituted phenyl. In certain embodiments, R.sup.B1 is substituted heteroaryl. In certain embodiments, R.sup.B1 is unsubstituted heteroaryl. In certain embodiments, R.sup.B1 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B1 is monocyclic heteroaryl. In certain embodiments, R.sup.B1 is 5-membered, monocyclic heteroaryl. In certain embodiments, R.sup.B1 is 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.B1 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.B1 is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.B1 is a nitrogen protecting group. In certain embodiments, R.sup.B1 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

(82) In certain embodiments, R.sup.B1 is a moiety of the formula:

(83) ##STR00167##
wherein L.sup.1b is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, and R.sup.A1b is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl. In certain embodiments, L.sup.1b is substituted alkylene. In certain embodiments, L.sup.1b is a moiety shown in Table 2. In certain embodiments, L.sup.1b is unsubstituted alkylene. In certain embodiments, L.sup.1b is a moiety shown in Table 1. In certain embodiments, L.sup.1b is substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1b is C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, L.sup.1b is C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, L.sup.1b is C.sub.1-6 perfluoroalkylene. In certain embodiments, L.sup.1b is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.1b is of the formula:

(84) ##STR00168##
In certain embodiments, L.sup.1b is of the formula:

(85) ##STR00169##
In certain embodiments, L is of the formula:

(86) ##STR00170##

(87) In certain embodiments, L.sup.1b is substituted heteroalkylene. In certain embodiments, L.sup.1b is unsubstituted heteroalkylene. In certain embodiments, L.sup.1b is a moiety shown in Table 3. In certain embodiments, L.sup.1b is substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.1b is C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, L.sup.1b is C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, L.sup.1b is unsubstituted C.sub.1-6 heteroalkylene. In certain embodiments, R.sup.A1b is substituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A1b is a moiety shown in Table 5. In certain embodiments, R.sup.A1b is C.sub.4-30 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.4-30 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.4-30 perfluoroalkyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A1b is a moiety shown in Table 4. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.4-30 alkyl. In certain embodiments, R.sup.A1b is substituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A1b is C.sub.7-24 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.7-24 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.7-24 perfluoroalkyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.7-24 alkyl. In certain embodiments, R.sup.A1b is substituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A1b is C.sub.9-19 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.9-19 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.9-19 perfluoroalkyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.9-19 alkyl. In certain embodiments, R.sup.A1b is substituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A1b is C.sub.4-30 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.4-30 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.4-30 perfluoroalkenyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A1b is a moiety shown in Table 6. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.4-30 alkenyl. In certain embodiments, R.sup.A1b is substituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A1b is C.sub.7-24 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.7-24 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.7-24 perfluoroalkenyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.7-24 alkenyl. In certain embodiments, R.sup.A1b is substituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A1b is C.sub.9-19 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.9-19 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.9-19 perfluoroalkenyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.9-19 alkenyl. In certain embodiments, R.sup.A1b is alkenyl described herein and includes one, two, three, four, five, or six C═C double bonds. In certain embodiments, R.sup.A1b is substituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A1b is C.sub.4-30 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.4-30 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.4-30 perfluoroalkynyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.4-30 alkynyl. In certain embodiments, R.sup.A1b is substituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A1b is C.sub.7-24 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.7-24 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.7-24 perfluoroalkynyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.7-24 alkynyl. In certain embodiments, R.sup.A1b is substituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A1b is C.sub.9-19 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A1b is C.sub.9-19 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A1b is C.sub.9-19 perfluoroalkynyl. In certain embodiments, R.sup.A1b is unsubstituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A1b is unsubstituted and unbranched C.sub.9-19 alkynyl.

(88) In certain embodiments, R.sup.B1 and R.sup.B2 are joined to form a substituted or unsubstituted, heterocyclic ring. In certain embodiments, R.sup.B1 and R.sup.B2 are joined to form a 3- to 7-membered, monocyclic heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur.

(89) In certain embodiments, R.sup.B1 and R.sup.B2 are joined to form a divalent moiety of the formula:

(90) ##STR00171##
wherein the moiety is substituted (e.g., with one or more halogen and/or oxo) or unsubstituted. In certain embodiments, R.sup.B1 and R.sup.B2 are joined to a divalent moiety of the formula:

(91) ##STR00172##
wherein the moiety is substituted (e.g., with one or more halogen) or unsubstituted. In certain embodiments, R.sup.B1 and R.sup.B2 are joined to form a substituted or unsubstituted, heteroaryl ring. In certain embodiments, R.sup.B1 and R.sup.B2 are joined to form a 5- to 6-membered, monocyclic heteroaryl ring, wherein one, two, or three atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B1 and R.sup.B2 are joined to form a 9- to 10-membered, bicyclic heteroaryl ring, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur.

(92) Formula (I) includes divalent linker L.sup.2a. In certain embodiments, L.sup.2a is substituted alkylene. In certain embodiments, L.sup.2a is a moiety shown in Table 2. In certain embodiments, L.sup.2a is unsubstituted alkylene. In certain embodiments, L.sup.2a is a moiety shown in Table 1. In certain embodiments, L.sup.2a is substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2a is C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, L.sup.2a is C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, L.sup.2a is C.sub.1-6 perfluoroalkylene. In certain embodiments, L.sup.2a is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2a is of the formula:

(93) ##STR00173##
In certain embodiments, L.sup.2a is of the formula:

(94) ##STR00174##
In certain embodiments, L.sup.2a is of the formula:

(95) ##STR00175##

(96) In certain embodiments, L.sup.2a is substituted heteroalkylene. In certain embodiments, L.sup.2a is unsubstituted heteroalkylene. In certain embodiments, L.sup.2a is a moiety shown in Table 3. In certain embodiments, L.sup.2a is substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.2a is C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, L.sup.2a is C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, L.sup.2a is unsubstituted C.sub.1-6 heteroalkylene.

(97) Formula (I) includes substituent R.sup.A2a. In certain embodiments, R.sup.A2 is substituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A2a is a moiety shown in Table 5. In certain embodiments, R.sup.A2a is C.sub.4-30 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.4-30 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.4-30 perfluoroalkyl.

(98) In certain embodiments, R.sup.A2a is unsubstituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A2a is a moiety shown in Table 4. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.4-30 alkyl. In certain embodiments, R.sup.A2a is substituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A2a is C.sub.7-24 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.7-24 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.7-24 perfluoroalkyl. In certain embodiments, R.sup.A2a is unsubstituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.7-24 alkyl. In certain embodiments, R.sup.A2a is substituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A2a is C.sub.9-19 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.9-19 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.9-19 perfluoroalkyl. In certain embodiments, R.sup.A2a is unsubstituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.9-19 alkyl. In certain embodiments, R.sup.A2a is substituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A2a is C.sub.4-30 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.4-30 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.4-30 perfluoroalkenyl. In certain embodiments, R.sup.A2a is unsubstituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A2a is a moiety shown in Table 6. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.4-30 alkenyl. In certain embodiments, R.sup.A2a is substituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A2a is C.sub.7-24 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.7-24 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.7-24 perfluoroalkenyl. In certain embodiments, R.sup.A2a is unsubstituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.7-24 alkenyl. In certain embodiments, R.sup.A2a is substituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A2a is C.sub.9-19 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.9-19 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.9-19 perfluoroalkenyl. In certain embodiments, R.sup.A2a is unsubstituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.9-19 alkenyl. In certain embodiments, R.sup.A2a is alkenyl described herein and includes one, two, three, four, five, or six C═C double bonds. In certain embodiments, R.sup.A2a is substituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A2a is C.sub.4-30 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.4-30 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.4-30 perfluoroalkynyl. In certain embodiments, R.sup.A2a is unsubstituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.4-30 alkynyl. In certain embodiments, R.sup.A2a is substituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A2a is C.sub.7-24 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.7-24 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.7-24 perfluoroalkynyl. In certain embodiments, R.sup.A2a is unsubstituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.7-24 alkynyl. In certain embodiments, R.sup.A2a is substituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A2a is C.sub.9-19 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A2a is C.sub.9-19 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A2a is C.sub.9-19 perfluoroalkynyl. In certain embodiments, R.sup.A2a is unsubstituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A2a is unsubstituted and unbranched C.sub.9-19 alkynyl.

(99) Formula (I) includes substituent R.sup.B2. In certain embodiments, R.sup.B2 is H. In certain embodiments, R.sup.B2 is substituted acyl. In certain embodiments, R.sup.B2 is unsubstituted acyl. In certain embodiments, R.sup.B2 is acetyl. In certain embodiments, R.sup.B2 is substituted alkyl. In certain embodiments, R.sup.B2 is unsubstituted alkyl. In certain embodiments, R.sup.B2 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B2 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B2 is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.B2 is substituted methyl. In certain embodiments, R.sup.B2 is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, R.sup.B2 is —CH.sub.3. In certain embodiments, R.sup.B2 is ethyl. In certain embodiments, R.sup.B2 is propyl. In certain embodiments, R.sup.B2 is butyl. In certain embodiments, R.sup.B2 is pentyl. In certain embodiments, R.sup.B2 is hexyl. In certain embodiments, R.sup.B2 is substituted alkenyl. In certain embodiments, R.sup.B2 is unsubstituted alkenyl. In certain embodiments, R.sup.B2 is substituted C.sub.1-6 alkenyl. In certain embodiments, R.sup.B2 is unsubstituted C.sub.1-6 alkenyl. In certain embodiments, R.sup.B2 is vinyl. In certain embodiments, R.sup.B2 is substituted alkynyl. In certain embodiments, R.sup.B2 is unsubstituted alkynyl. In certain embodiments, R.sup.B2 is substituted C.sub.1-6 alkynyl. In certain embodiments, R.sup.B2 is unsubstituted C.sub.1-6 alkynyl. In certain embodiments, R.sup.B2 is substituted carbocyclyl. In certain embodiments, R.sup.B2 is unsubstituted carbocyclyl. In certain embodiments, R.sup.B2 is saturated carbocyclyl. In certain embodiments, R.sup.B2 is unsaturated carbocyclyl. In certain embodiments, R.sup.B2 is monocyclic carbocyclyl. In certain embodiments, R.sup.B2 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.B2 is substituted heterocyclyl. In certain embodiments, R.sup.B2 is unsubstituted heterocyclyl. In certain embodiments, R.sup.B2 is saturated heterocyclyl. In certain embodiments, R.sup.B2 is unsaturated heterocyclyl. In certain embodiments, R.sup.B2 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B2 is monocyclic heterocyclyl. In certain embodiments, R.sup.B2 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.B2 is substituted aryl. In certain embodiments, R.sup.B2 is unsubstituted aryl. In certain embodiments, R.sup.B2 is 6- to 10-membered aryl. In certain embodiments, R.sup.B2 is substituted phenyl. In certain embodiments, R.sup.B2 is unsubstituted phenyl. In certain embodiments, R.sup.B2 is substituted heteroaryl. In certain embodiments, R.sup.B2 is unsubstituted heteroaryl. In certain embodiments, R.sup.B2 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B2 is monocyclic heteroaryl. In certain embodiments, R.sup.B2 is 5-membered, monocyclic heteroaryl. In certain embodiments, R.sup.B2 is 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.B2 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.B2 is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.B2 is a nitrogen protecting group. In certain embodiments, R.sup.B2 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

(100) In certain embodiments, R.sup.B2 is a moiety of the formula:

(101) ##STR00176##
wherein L.sup.2b is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, and R.sup.A2b is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl. In certain embodiments, L.sup.2b is substituted alkylene. In certain embodiments, L.sup.2b is a moiety shown in Table 2. In certain embodiments, L.sup.2b is unsubstituted alkylene. In certain embodiments, L.sup.2b is a moiety shown in Table 1. In certain embodiments, L.sup.2b is substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2b is C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, L.sup.2b is C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, L.sup.2b is C.sub.1-6 perfluoroalkylene. In certain embodiments, L.sup.2b is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.2b is of the formula:

(102) ##STR00177##
In certain embodiments, L.sup.2b is of the formula:

(103) ##STR00178##
In certain embodiments, L.sup.2b is of the formula:

(104) ##STR00179##

(105) In certain embodiments, L.sup.2b is substituted heteroalkylene. In certain embodiments, L.sup.2b is unsubstituted heteroalkylene. In certain embodiments, L.sup.2b is a moiety shown in Table 3. In certain embodiments, L.sup.2b is substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.2b is C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, L.sup.2b is C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, L.sup.2b is unsubstituted C.sub.1-6 heteroalkylene. In certain embodiments, R.sup.A2b is substituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A2b is a moiety shown in Table 5. In certain embodiments, R.sup.A2b is C.sub.4-30 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.4-30 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.4-30 perfluoroalkyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A2b is a moiety shown in Table 4. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.4-30 alkyl. In certain embodiments, R.sup.A2b is substituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A2b is C.sub.7-24 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.7-24 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.7-24 perfluoroalkyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.7-24 alkyl. In certain embodiments, R.sup.A2b is substituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A2b is C.sub.9-19 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.9-19 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.9-19 perfluoroalkyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.9-19 alkyl. In certain embodiments, R.sup.A2b is substituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A2b is C.sub.4-30 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.4-30 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.4-30 perfluoroalkenyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A2b is a moiety shown in Table 6. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.4-30 alkenyl. In certain embodiments, R.sup.A2b is substituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A2b is C.sub.7-24 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.7-24 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.7-24 perfluoroalkenyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.7-24 alkenyl. In certain embodiments, R.sup.A2b is substituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A2b is C.sub.9-19 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.9-19 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.9-19 perfluoroalkenyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.9-19 alkenyl. In certain embodiments, R.sup.A2b is alkenyl described herein and includes one, two, three, four, five, or six C═C double bonds. In certain embodiments, R.sup.A2b is substituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A2b is C.sub.4-30 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.4-30 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.4-30 perfluoroalkynyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.4-30 alkynyl. In certain embodiments, R.sup.A2b is substituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A2b is C.sub.7-24 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.7-24 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.7-24 perfluoroalkynyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.7-24 alkynyl. In certain embodiments, R.sup.A2b is substituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A2b is C.sub.9-19 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A2b is C.sub.9-19 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A2b is C.sub.9-19 perfluoroalkynyl. In certain embodiments, R.sup.A2b is unsubstituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A2b is unsubstituted and unbranched C.sub.9-19 alkynyl.

(106) In Formula (I), any two of L.sup.1a, L.sup.2a, L.sup.1b, and L.sup.2b may be the same or different. In certain embodiments, L.sup.1a and L.sup.2a are the same. In certain embodiments, each of L.sup.1a and L.sup.2a is independently substituted or unsubstituted alkylene. In certain embodiments, each of L.sup.1a and L.sup.2a is of the formula:

(107) ##STR00180##
In certain embodiments, each of L.sup.1a and L.sup.2a is of the formula:

(108) ##STR00181##
In certain embodiments, each of L.sup.1a and L.sup.2a is of the formula:

(109) ##STR00182##
In certain embodiments, L.sup.1a, L.sup.2a, and L.sup.1b are the same. In certain embodiments, L.sup.1a, L.sup.2a, L.sup.1b, and L.sup.2b are the same.

(110) In Formula (I), any two of R.sup.1a, R.sup.A2a, R.sup.1b, and R.sup.A2b may be the same or different. In certain embodiments, R.sup.A1a and R.sup.A2a are the same. In certain embodiments, at least one of R.sup.A1a and R.sup.A2a is substituted or unsubstituted, C.sub.7-24 alkyl. In certain embodiments, at least one of R.sup.A1a and R.sup.A2a is substituted or unsubstituted, C.sub.9-19 alkyl. In certain embodiments, at least one of R.sup.A1a and R.sup.A2a is substituted or unsubstituted, C.sub.7-24 alkenyl. In certain embodiments, at least one of R.sup.A1a and R.sup.A2a is substituted or unsubstituted, C.sub.9-19 alkenyl. In certain embodiments, R.sup.A1a, R.sup.A2a and R.sup.A1b are the same. In certain embodiments, R.sup.A1a, R.sup.A2a, R.sup.A1b, and R.sup.A2b are the same.

(111) In certain embodiments, the compound of Formula (I) is of Formula (I-C):

(112) ##STR00183##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein each instance of t is 2, 3, 4, 5, or 6.

(113) In certain embodiments, the compound of Formula (I) is of Formula (I-D):

(114) ##STR00184##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(115) In certain embodiments, the compound of Formula (I) is of Formula (I-E):

(116) ##STR00185##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein each instance of t is 2, 3, 4, 5, or 6; and each instance of r is 2, 3, 4, 5, or 6.

(117) In certain embodiments, the compound of Formula (I) is of Formula (I-F):

(118) ##STR00186##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(119) In certain embodiments, the compound of Formula (I) is of Formula (I-G):

(120) ##STR00187##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein:

(121) R.sup.B4 is substituted or unsubstituted C.sub.1-6 alkyl; and

(122) R.sup.A4a is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl.

(123) In certain embodiments, a compound of Formula (I) is a compound of any one of Formulae (I-C) to (I-G), wherein each of R.sup.B1 and R.sup.B2 is H or substituted or unsubstituted, C.sub.1-6 alkyl (e.g., methyl).

(124) In certain embodiments, the compound of Formula (I) is of Formula (I-A):

(125) ##STR00188##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(126) In certain embodiments, the compound of Formula (I) is of Formula (I-H):

(127) ##STR00189##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein each instance of t is 2, 3, 4, 5, or 6.

(128) In certain embodiments, the compound of Formula (I) is of Formula (I-I):

(129) ##STR00190##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(130) In certain embodiments, the compound of Formula (I) is of Formula (I-J):

(131) ##STR00191##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein each instance of t is 2, 3, 4, 5, or 6; and each instance of r is 2, 3, 4, 5, or 6.

(132) In certain embodiments, the compound of Formula (I) is of Formula (I-K):

(133) ##STR00192##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(134) In certain embodiments, the compound of Formula (I) is of Formula (I-L):

(135) ##STR00193##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein:

(136) R.sup.B4 is substituted or unsubstituted C.sub.1-6 alkyl; and

(137) R.sup.A4a is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl.

(138) In certain embodiments, a compound of Formula (I) is a compound of any one of Formulae (I-A) and (I-H) to (I-L), wherein R.sup.B2 is H or substituted or unsubstituted, C.sub.1-6 alkyl (e.g., methyl).

(139) In certain embodiments, the compound of Formula (I) is of Formula (I-B):

(140) ##STR00194##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(141) In certain embodiments, the compound of Formula (I) is of the formula:

(142) ##STR00195##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein each instance of t is 2, 3, 4, 5, or 6.

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

(144) ##STR00196##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(145) In certain embodiments, the compound of Formula (I) is of the formula:

(146) ##STR00197##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein each instance of t is 2, 3, 4, 5, or 6; and each instance of r is 2, 3, 4, 5, or 6.

(147) In certain embodiments, the compound of Formula (I) is of the formula:

(148) ##STR00198##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(149) In certain embodiments, the compound of Formula (I) is of the formula:

(150) ##STR00199##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein:

(151) R.sup.B4 is substituted or unsubstituted C.sub.1-6 alkyl; and

(152) R.sup.A4a is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl.

(153) In certain embodiments, the compound of Formula (I) is of the formula:

(154) ##STR00200##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein:

(155) R.sup.A4a is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl; and

(156) R.sup.A4b is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl.

(157) Exemplary compounds of Formula (I) include, but are not limited to:

(158) ##STR00201## ##STR00202## ##STR00203##
and salts, hydrates, solvates, polymorphs, tautomers, stereoisomers, and isotopically labeled derivatives thereof.

(159) In another aspect, the present disclosure provides compounds of Formula (II):

(160) ##STR00204##
and salts, hydrates, solvates, polymorphs, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein:

(161) Formula (II) includes divalent linker L.sup.3a. In certain embodiments, L.sup.3a is substituted alkylene. In certain embodiments, L.sup.3a is a moiety shown in Table 2. In certain embodiments, L.sup.3a is unsubstituted alkylene. In certain embodiments, L.sup.3a is a moiety shown in Table 1. In certain embodiments, L.sup.3a is substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.3a is C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, L.sup.3a is C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, L.sup.3a is C.sub.1-6 perfluoroalkylene. In certain embodiments, L.sup.3a is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.3a is of the formula:

(162) ##STR00205##
In certain embodiments, L.sup.3a is of the formula:

(163) ##STR00206##
In certain embodiments, L.sup.3a is of the formula:

(164) ##STR00207##

(165) In certain embodiments, L.sup.3a is substituted heteroalkylene. In certain embodiments, L.sup.3a is unsubstituted heteroalkylene. In certain embodiments, L.sup.3a is a moiety shown in Table 3. In certain embodiments, L.sup.3a is substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.3a is C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, L.sup.3a is C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, L.sup.3a is unsubstituted C.sub.1-6 heteroalkylene.

(166) Formula (II) includes substituent R.sup.A3a. In certain embodiments, R.sup.A3a is substituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A3a is a moiety shown in Table 5. In certain embodiments, R.sup.A3a is C.sub.4-30 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.4-30 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.4-30 perfluoroalkyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A3a is a moiety shown in Table 4. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.4-30 alkyl. In certain embodiments, R.sup.A3a is substituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A3a is C.sub.7-24 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.7-24 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.7-24 perfluoroalkyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.7-24 alkyl. In certain embodiments, R.sup.A3a is substituted C.sub.9-19 alkyl.

(167) In certain embodiments, R.sup.A3a is C.sub.9-19 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.9-19 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.9-19 perfluoroalkyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.9-19 alkyl.

(168) In certain embodiments, R.sup.A3a is substituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3a is C.sub.4-30 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.4-30 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.4-30 perfluoroalkenyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3a is a moiety shown in Table 6. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3a is substituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3a is C.sub.7-24 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.7-24 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.7-24 perfluoroalkenyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3a is substituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3a is C.sub.9-19 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.9-19 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.9-19 perfluoroalkenyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3a is alkenyl described herein and includes one, two, three, four, five, or six C═C double bonds.

(169) In certain embodiments, R.sup.A3a is substituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A3a is C.sub.4-30 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.4-30 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.4-30 perfluoroalkynyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.4-30 alkynyl. In certain embodiments, R.sup.A3a is substituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A3a is C.sub.7-24 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.7-24 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.7-24 perfluoroalkynyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.7-24 alkynyl. In certain embodiments, R.sup.A3a is substituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A3a is C.sub.9-19 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3a is C.sub.9-19 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3a is C.sub.9-19 perfluoroalkynyl. In certain embodiments, R.sup.A3a is unsubstituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A3a is unsubstituted and unbranched C.sub.9-19 alkynyl.

(170) Formula (II) includes divalent linker L.sup.3b. In certain embodiments, L.sup.3b is substituted alkylene. In certain embodiments, L.sup.3b is a moiety shown in Table 2. In certain embodiments, L.sup.3b is unsubstituted alkylene. In certain embodiments, L.sup.3b is a moiety shown in Table 1. In certain embodiments, L.sup.3b is substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.3b is C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, L.sup.3b is C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, L.sup.3b is C.sub.1-6 perfluoroalkylene. In certain embodiments, L.sup.3b is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.3b is of the formula:

(171) ##STR00208##
In certain embodiments, L.sup.3b is of the formula:

(172) ##STR00209##
In certain embodiments, L.sup.3b is of the formula:

(173) ##STR00210##

(174) In certain embodiments, L.sup.3b is substituted heteroalkylene. In certain embodiments, L.sup.3b is unsubstituted heteroalkylene. In certain embodiments, L.sup.3b is a moiety shown in Table 3. In certain embodiments, L.sup.3b is substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.3b is C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, L.sup.3b is C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, L.sup.3b is unsubstituted C.sub.1-6 heteroalkylene.

(175) Formula (II) includes substituent R.sup.A3b. In certain embodiments, R.sup.A3b is substituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A3b is a moiety shown in Table 5. In certain embodiments, R.sup.A3b is C.sub.4-30 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3b is C.sub.4-30 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.4-30 perfluoroalkyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A3b is a moiety shown in Table 4. In certain embodiments, R.sup.3b is unsubstituted and unbranched C.sub.4-30 alkyl. In certain embodiments, R.sup.A3b is substituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A3b is C.sub.7-24 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3b is C.sub.7-24 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.7-24 perfluoroalkyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A3b is unsubstituted and unbranched C.sub.7-24 alkyl. In certain embodiments, R.sup.A3b is substituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A3b is C.sub.9-19 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3b is C.sub.9-19 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.9-19 perfluoroalkyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A3b is unsubstituted and unbranched C.sub.9-19 alkyl.

(176) In certain embodiments, R.sup.A3b is substituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3b is C.sub.4-30 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A3b is C.sub.4-30 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.4-30 perfluoroalkenyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3b is a moiety shown in Table 6. In certain embodiments, R.sup.A3b is unsubstituted and unbranched C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3b is substituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3b is C.sub.7-24 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.3b is C.sub.7-24 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.7-24 perfluoroalkenyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3b is unsubstituted and unbranched C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3b is substituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3b is C.sub.9-19 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A3b is C.sub.9-19 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.9-19 perfluoroalkenyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3b is unsubstituted and unbranched C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3b is alkenyl described herein and includes one, two, three, four, five, or six C═C double bonds.

(177) In certain embodiments, R.sup.A3b is substituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A3b is C.sub.4-30 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3b is C.sub.4-30 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.4-30 perfluoroalkynyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.3b is unsubstituted and unbranched C.sub.4-30 alkynyl. In certain embodiments, R.sup.3b is substituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A3b is C.sub.7-24 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3b is C.sub.7-24 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.7-24 perfluoroalkynyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A3b is unsubstituted and unbranched C.sub.7-24 alkynyl. In certain embodiments, R.sup.A3b is substituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A3b is C.sub.9-19 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3b is C.sub.9-19 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3b is C.sub.9-19 perfluoroalkynyl. In certain embodiments, R.sup.A3b is unsubstituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A3b is unsubstituted and unbranched C.sub.9-19 alkynyl.

(178) Formula (I) includes substituent R.sup.B3. In certain embodiments, R.sup.B3 is H. In certain embodiments, R.sup.B3 is substituted acyl. In certain embodiments, R.sup.B3 is unsubstituted acyl. In certain embodiments, R.sup.B3 is acetyl. In certain embodiments, R.sup.B3 is substituted alkyl. In certain embodiments, R.sup.B3 is unsubstituted alkyl. In certain embodiments, R.sup.B3 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B3 is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.B3 is substituted methyl. In certain embodiments, R.sup.B3 is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, R.sup.B3 is —CH.sub.3. In certain embodiments, R.sup.B3 is ethyl. In certain embodiments, R.sup.B3 is propyl. In certain embodiments, R.sup.B3 is butyl. In certain embodiments, R.sup.B3 is pentyl. In certain embodiments, R.sup.B3 is hexyl. In certain embodiments, R.sup.B3 is substituted alkenyl. In certain embodiments, R.sup.B3 is unsubstituted alkenyl. In certain embodiments, R.sup.B3 is substituted C.sub.1-6 alkenyl. In certain embodiments, R.sup.B3 is unsubstituted C.sub.1-6 alkenyl. In certain embodiments, R.sup.B3 is vinyl. In certain embodiments, R.sup.B3 is substituted alkynyl. In certain embodiments, R.sup.B3 is unsubstituted alkynyl. In certain embodiments, R.sup.B3 is substituted C.sub.1-6 alkynyl. In certain embodiments, R.sup.B3 is unsubstituted C.sub.1-6 alkynyl. In certain embodiments, R.sup.B3 is substituted carbocyclyl. In certain embodiments, R.sup.B3 is unsubstituted carbocyclyl. In certain embodiments, R.sup.B3 is saturated carbocyclyl. In certain embodiments, R.sup.B3 is unsaturated carbocyclyl. In certain embodiments, R.sup.B3 is monocyclic carbocyclyl. In certain embodiments, R.sup.B3 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, R.sup.B3 is substituted heterocyclyl. In certain embodiments, R.sup.B3 is unsubstituted heterocyclyl. In certain embodiments, R.sup.B3 is saturated heterocyclyl. In certain embodiments, R.sup.B3 is unsaturated heterocyclyl. In certain embodiments, R.sup.B3 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B3 is monocyclic heterocyclyl. In certain embodiments, R.sup.B3 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, R.sup.B3 is substituted aryl. In certain embodiments, R.sup.B3 is unsubstituted aryl. In certain embodiments, R.sup.B3 is 6- to 10-membered aryl. In certain embodiments, R.sup.B3 is substituted phenyl. In certain embodiments, R.sup.B3 is unsubstituted phenyl. In certain embodiments, R.sup.B3 is substituted heteroaryl. In certain embodiments, R.sup.B3 is unsubstituted heteroaryl. In certain embodiments, R.sup.B3 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, R.sup.B3 is monocyclic heteroaryl. In certain embodiments, R.sup.B3 is 5-membered, monocyclic heteroaryl. In certain embodiments, R.sup.B3 is 6-membered, monocyclic heteroaryl. In certain embodiments, R.sup.B3 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.B3 is 9- or 10-membered, bicyclic heteroaryl. In certain embodiments, R.sup.B3 is a nitrogen protecting group. In certain embodiments, R.sup.B3 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

(179) In certain embodiments, R.sup.B3 is a moiety of the formula:

(180) ##STR00211##
wherein L.sup.3c is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, and R.sup.3c is substituted or unsubstituted, C.sub.4-30 alkyl, substituted or unsubstituted, C.sub.4-30 alkenyl, or substituted or unsubstituted, C.sub.4-30 alkynyl. In certain embodiments, L.sup.3c is substituted alkylene. In certain embodiments, L.sup.3c is a moiety shown in Table 2. In certain embodiments, L.sup.3c is unsubstituted alkylene. In certain embodiments, L.sup.3c is a moiety shown in Table 1. In certain embodiments, L.sup.3c is substituted C.sub.1-6 alkylene. In certain embodiments, L.sup.3c is C.sub.1-6 alkylene substituted with at least one halogen. In certain embodiments, L.sup.3c is C.sub.1-6 alkylene substituted with at least one fluorine. In certain embodiments, L.sup.3c is C.sub.1-6 perfluoroalkylene. In certain embodiments, L.sup.3c is unsubstituted C.sub.1-6 alkylene. In certain embodiments, L.sup.3c is of the formula:

(181) ##STR00212##
In certain embodiments, L.sup.3c is of the formula:

(182) ##STR00213##
In certain embodiments, L.sup.3c is of the formula:

(183) ##STR00214##

(184) In certain embodiments, L.sup.3c is substituted heteroalkylene. In certain embodiments, L.sup.3c is unsubstituted heteroalkylene. In certain embodiments, L.sup.3c is a moiety shown in Table 3. In certain embodiments, L.sup.3c is substituted C.sub.1-6 heteroalkylene. In certain embodiments, L.sup.3c is C.sub.1-6 heteroalkylene substituted with at least one halogen. In certain embodiments, L.sup.3c is C.sub.1-6 heteroalkylene substituted with at least one fluorine. In certain embodiments, L.sup.3c is unsubstituted C.sub.1-6 heteroalkylene. In certain embodiments, R.sup.A3c is substituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A3c is a moiety shown in Table 5. In certain embodiments, R.sup.A3c is C.sub.4-30 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.4-30 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.4-30 perfluoroalkyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.4-30 alkyl. In certain embodiments, R.sup.A3c is a moiety shown in Table 4. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.4-30 alkyl. In certain embodiments, R.sup.3c is substituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A3c is C.sub.7-24 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.7-24 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.7-24 perfluoroalkyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.7-24 alkyl. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.7-24 alkyl. In certain embodiments, R.sup.A3c is substituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A3c is C.sub.9-19 alkyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.9-19 alkyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.9-19 perfluoroalkyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.9-19 alkyl. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.9-19 alkyl.

(185) In certain embodiments, R.sup.3c is substituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3c is C.sub.4-30 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.4-30 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.4-30 perfluoroalkenyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3c is a moiety shown in Table 6. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.4-30 alkenyl. In certain embodiments, R.sup.A3c is substituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3c is C.sub.7-24 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.7-24 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.7-24 perfluoroalkenyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.7-24 alkenyl. In certain embodiments, R.sup.A3c is substituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3c is C.sub.9-19 alkenyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.9-19 alkenyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.9-19 perfluoroalkenyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3c is alkenyl described herein and includes one, two, three, four, five, or six C═C double bonds.

(186) In certain embodiments, R.sup.3c is substituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A3c is C.sub.4-30 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.4-30 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.4-30 perfluoroalkynyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.4-30 alkynyl. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.4-30 alkynyl. In certain embodiments, R.sup.A3c is substituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A3c is C.sub.7-24 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.7-24 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.7-24 perfluoroalkynyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.7-24 alkynyl. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.7-24 alkynyl. In certain embodiments, R.sup.3c is substituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A3c is C.sub.9-19 alkynyl substituted with one or more halogen. In certain embodiments, R.sup.A3c is C.sub.9-19 alkynyl substituted with one or more fluorine. In certain embodiments, R.sup.A3c is C.sub.9-19 perfluoroalkynyl. In certain embodiments, R.sup.A3c is unsubstituted C.sub.9-19 alkynyl. In certain embodiments, R.sup.A3c is unsubstituted and unbranched C.sub.9-19 alkynyl.

(187) In Formula (II), any two of L.sup.3a, L.sup.3b, and L.sup.3c may be the same or different. In certain embodiments, L.sup.3a and L.sup.3b are the same. In certain embodiments, each of L.sup.3a and L.sup.3b is independently substituted or unsubstituted alkylene. In certain embodiments, each of L.sup.3a and L.sup.3b is of the formula:

(188) ##STR00215##
In certain embodiments, each of L.sup.3a and L.sup.3b is of the formula:

(189) ##STR00216##
In certain embodiments, each of L.sup.3a and L.sup.3b is of the formula:

(190) ##STR00217##
In certain embodiments, L.sup.3a, L.sup.3b, and L.sup.3c are the same.

(191) In Formula (II), any two of R.sup.A3a, R.sup.A3b, and R.sup.A3c may be the same or different. In certain embodiments, R.sup.A3a and R.sup.A3b are the same. In certain embodiments, at least one of R.sup.A3a and R.sup.A3b is substituted or unsubstituted, C.sub.7-24 alkyl. In certain embodiments, at least one of R.sup.A3a and R.sup.A3b is substituted or unsubstituted, C.sub.9-19 alkyl. In certain embodiments, at least one of R.sup.A3a and R.sup.A3b is substituted or unsubstituted, C.sub.7-24 alkenyl. In certain embodiments, at least one of R.sup.A3a and R.sup.A3b is substituted or unsubstituted, C.sub.9-19 alkenyl. In certain embodiments, R.sup.A3a, R.sup.A3b and R.sup.A3c are the same.

(192) In certain embodiments, the compound of Formula (II) is of formula:

(193) ##STR00218##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein each instance of s is 2, 3, 4, 5, or 6.

(194) In certain embodiments, the compound of Formula (II) is of the formula:

(195) ##STR00219##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(196) In certain embodiments, the compound of Formula (II) is of Formula (II-A):

(197) ##STR00220##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(198) In certain embodiments, the compound of Formula (I) is of the formula:

(199) ##STR00221##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof, wherein each instance of s is 2, 3, 4, 5, or 6.

(200) In certain embodiments, the compound of Formula (II) is of the formula:

(201) ##STR00222##
or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof.

(202) Exemplary compounds of Formula (II) include, but are not limited to:

(203) ##STR00223## ##STR00224##
and salts, hydrates, solvates, polymorphs, tautomers, stereoisomers, and isotopically labeled derivatives thereof.

(204) In another aspect, the present disclosure provides compounds listed in Table 6A, and salts, hydrates, solvates, polymorphs, tautomers, stereoisomers, and isotopically labeled derivatives thereof.

(205) TABLE-US-00007 TABLE 6A Single-tailed lipidoids of the present disclosure embedded image 1C18Oleic 3C18Oleic 30C18Oleic 1C18 1C14 0 1C16 1C18Elaidic 1C15 1C18Oleic 3C14 3C15 3C16 3C17 3C18 30C14 0 30C15 30C16 30C17 30C18

(206) In certain embodiments, a compound described herein is a compound of Formula (I), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a compound described herein is a compound of Formula (I), or a salt thereof. In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound described herein is a compound of Formula (II), or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a compound described herein is a compound of Formula (II), or a salt thereof. In certain embodiments, a compound described herein is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiments, a compound described herein is a compound listed in Table 6A, or a salt, hydrate, solvate, polymorph, tautomer, stereoisomer, and isotopically labeled derivative thereof. In certain embodiments, a compound described herein is a compound listed in Table 6A, or a salt thereof. In certain embodiments, a compound described herein is a compound listed in Table 6A, or a pharmaceutically acceptable salt thereof.

(207) The compounds described herein may be useful in delivering an agent, such as a polynucleotide (e.g., DNA (e.g., plasmid DNA) or RNA (e.g., an siRNA, mRNA), or a combination thereof), to a subject, tissue, or cell. The compounds described herein may also be useful in treating and/or preventing a disease (e.g., a genetic disease, proliferative disease, hematological disease, or neurological disease) in a subject in need thereof. In certain embodiments, the compounds described herein are useful in gene therapy.

(208) Delivery of an agent to a subject, tissue, or cell using multi-tailed lipidoids have been reported. However, the toxicity of lipidoids still remain a problem (Lv et al., Control. Release, 114, 100-109 (2006); Ma et. al., Biochem. Biophys. Res. Commun., 330, 755-759 (2005); Akhtar et al., Adv. Drug Deliv. Rev., 59, 164-182 (2007)). For example, polyamine-acrylamide derived lipidoids do not readily hydrolyze under physiological conditions due to their amide bond linkage. Therefore, these polyamine-acrylamides accumulate in the kidneys at sometimes hazardous levels due to inefficient renal clearance (Scheme 1).

(209) ##STR00244##

(210) Polyamine-acrylate derived lipidoids typically degrade more readily under physiological conditions than polyamine-acrylamide derived lipidoids, due to the hydrolysable ester bond linkage. However, current polyamine-acrylate derived lipidoids include “external” ester moieties R—O—C(═O)— (wherein R is a lipid moiety) and may hydrolyze into aliphatic alcohols ROH due to the “external” orientation of the ester (Scheme 2), and the resulting aliphatic alcohols are often toxic.

(211) ##STR00245##

(212) The compounds of the present disclosure are advantageous over reported lipidoids in delivering an agent to a subject, tissue, or cell. Instead of an amide linkage or an “external” ester linkage, the compounds described herein include “internal” ester linkage, i.e., a lipid moiety (R) of a compound described herein is directly attached to a —C(═O)—O— moiety to form an R—C(═O)—O— moiety (“internal”), rather than to form an R—O—C(═O)— moiety (“external”). By “internalizing” the ester linkage, the compounds of the disclosure may hydrolyze into carboxylic acids (e.g., fatty acids), which are typically non-toxic, thereby decreasing the toxicity associated with lipidoid delivery systems (see, e.g., Scheme 3). Therefore, the compounds of the disclosure are typically biodegradable and non-toxic.

(213) ##STR00246##

(214) In certain embodiments, a compound Formula (I) is a compound of formula:

(215) ##STR00247##
or a salt thereof, wherein L.sup.X, L.sup.1a, L.sup.2a, R.sup.X1, R.sup.A1a, and R.sup.A2a are as defined herein.

(216) In certain embodiments, a compound Formula (I) is a compound of formula:

(217) ##STR00248##
or a salt thereof, wherein f is 2, 3, 4, or 5, and wherein R.sup.X, R.sup.A1a, and R.sup.A2a are as defined herein.

(218) In certain embodiments, a compound Formula (I) is a compound of formula:

(219) ##STR00249## ##STR00250## ##STR00251##
Methods of Preparing the Compounds and Compounds Prepared by the Methods

(220) Compounds described herein may be prepared using esterification (e.g., Methods A and D), alkylation (e.g., Methods B and E), or reductive amination (e.g., Methods C and F) reactions. In another aspect, the present disclosure also provides methods of preparing the compounds described herein. In certain embodiments, described herein are methods of preparing the compounds of Formula (I), and salts, stereoisomers, and isotopically labeled derivatives thereof (Method A), the methods including esterifying an alcohol of Formula (A), or a salt, stereoisomer, and isotopically labeled derivative thereof, with a carboxylic acid of Formula (B), or a salt, stereoisomer, and isotopically labeled derivative thereof:

(221) ##STR00252##

(222) In certain embodiments, described herein are methods of preparing the compounds of Formula (I), and salts, stereoisomers, and isotopically labeled derivatives thereof (Method B), the methods including alkylating an amine of Formula (C), or a salt, stereoisomer, and isotopically labeled derivative thereof, with a compound of Formula (D), or a salt, stereoisomer, and isotopically labeled derivative thereof:

(223) ##STR00253##
wherein Y is a leaving group.

(224) Formula (D) includes substituent Y. In certain embodiments, Y is Cl, Br, I, or —OS(═O),R.sup.Y, wherein u is 1 or 2; and R.sup.Y 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, or substituted or unsubstituted heteroaryl. In certain embodiments, Y is Cl. In certain embodiments, Y is Br. In certain embodiments, Y is I (iodine). In certain embodiments, Y is —OS(═O).sub.uR.sup.Y. In certain embodiments, Y is —OS(═O)R.sup.Y. In certain embodiments, Y is —OS(═O).sub.2R.sup.Y. In certain embodiments, Y is —OTs, —OMs, —OBs, or —OTf.

(225) In certain embodiments, u is 1. In certain embodiments, u is 2.

(226) In certain embodiments, R.sup.Y is substituted alkyl. In certain embodiments, R.sup.Y is unsubstituted alkyl. In certain embodiments, R.sup.Y is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.Y is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.Y is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.Y is substituted methyl. In certain embodiments, R.sup.Y is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, R.sup.Y is —CH.sub.3. In certain embodiments, R.sup.Y is ethyl. In certain embodiments, R.sup.Y is propyl. In certain embodiments, R.sup.Y is butyl. In certain embodiments, R.sup.Y is pentyl. In certain embodiments, R.sup.Y is hexyl.

(227) In certain embodiments, described herein are methods of preparing the compounds of Formula (I), and salts, stereoisomers, and isotopically labeled derivatives thereof (Method C), the methods including reacting an amine of Formula (C), or a salt thereof, with an aldehyde of Formula (K), or a salt thereof, in the presence of a reductant:

(228) ##STR00254##

(229) 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), 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., isopropanol), or butanol. In certain embodiments, the reductant is H.sub.2. In certain embodiments, the reductant is commercially available.

(230) In certain embodiments, described herein are methods of preparing the compounds of Formula (II), and salts, stereoisomers, and isotopically labeled derivatives thereof (Method D), the methods including esterifying an alcohol of Formula (E), or a salt, stereoisomer, and isotopically labeled derivative thereof, with a carboxylic acid of Formula (F), or a salt, stereoisomer, and isotopically labeled derivative thereof:

(231) ##STR00255##

(232) In certain embodiments, described herein are methods of preparing the compounds of Formula (II), and salts, stereoisomers, and isotopically labeled derivatives thereof (Method E), the methods including alkylating an amine of Formula (G), or a salt, stereoisomer, and isotopically labeled derivative thereof, with a compound of Formula (H), or a salt, stereoisomer, and isotopically labeled derivative thereof:

(233) ##STR00256##
wherein Z is a leaving group.

(234) Formula (H) includes substituent Z. In certain embodiments, Z is Cl, Br, I, or —OS(═O).sub.vR.sup.Z, wherein v is 1 or 2; and R.sup.Z 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, or substituted or unsubstituted heteroaryl. In certain embodiments, Z is Cl. In certain embodiments, Z is Br. In certain embodiments, Z is I (iodine). In certain embodiments, Z is —OS(═O).sub.vR.sup.Z. In certain embodiments, Z is —OS(═O)R.sup.Z. In certain embodiments, Z is —OS(═O).sub.2R.sup.Z. In certain embodiments, Z is —OTs, —OMs, —OBs, or —OTf.

(235) In certain embodiments, v is 1. In certain embodiments, v is 2.

(236) In certain embodiments, R.sup.Z is substituted alkyl. In certain embodiments, R.sup.Z is unsubstituted alkyl. In certain embodiments, R.sup.Z is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.Z is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.Z is C.sub.1-6 alkyl substituted with at least one halogen. In certain embodiments, R.sup.Z is substituted methyl. In certain embodiments, R.sup.Z is —CH.sub.2F, —CHF.sub.2, or —CF.sub.3. In certain embodiments, R.sup.Z is —CH.sub.3. In certain embodiments, R.sup.Z is ethyl. In certain embodiments, R.sup.Z is propyl. In certain embodiments, R.sup.Z is butyl. In certain embodiments, R.sup.Z is pentyl. In certain embodiments, R.sup.Z is hexyl.

(237) In certain embodiments, described herein are methods of preparing the compounds of Formula (II), and salts, stereoisomers, and isotopically labeled derivatives thereof (Method F), the methods including reacting an amine of Formula (G), or a salt thereof, with an aldehyde of Formula (J), or a salt thereof, in the presence of a reductant:

(238) ##STR00257##

(239) Certain embodiments of a compound of Formula (I) may be prepared according to Scheme 4. In certain embodiments, the X is a compound of formula:

(240) ##STR00258##
wherein each instance of p is independently 1, 2, 3, 4, 5, or 6. For example, X may be a bis-lysine diketopiperzine based moiety, of formula:

(241) ##STR00259##

(242) ##STR00260##

(243) Thus, in another aspect, described herein is a method of preparing the compound of Formula (I), or a salt, stereoisomer, or isotopically labeled derivative thereof, the method comprising esterifying an alcohol of Formula (S):

(244) ##STR00261##
or a salt, stereoisomer, or isotopically labeled derivative thereof, with a carboxylic acid of Formula (B):

(245) ##STR00262##
or a salt, stereoisomer, or isotopically labeled derivative thereof, wherein X, L.sup.X, L.sup.1a, L.sup.2a, and R.sup.X1 are as described herein, to provide a compound of Formula (I). In some embodiments, the step of esterifying is performed in the presence of a base. In some embodiments, the base is an organic base. In certain embodiments, the organic base is an aliphatic amine or aromatic amine. In certain embodiments, the organic base is a primary amine, secondary amine, or tertiary amine. In certain embodiments, the organic base is triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,6-lutidine, or 4-dimethylaminopyridine (DMAP). In some embodiments, the step of esterifying is performed in the presence of a carbodiimide (e.g., N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or N,N′-diisopropylcarbodiimide (DIC)). In some embodiments, the step of esterigying is performed in the presence of a catalyst (e.g., DMAP, 1-hydroxybenzotriazole (HOBt), or 1-hydroxy-7-azabenzotriazole (HOAt)).

(246) In another aspect, the method of preparing a compound of Formula (I) further comprises deprotecting a compound of Formula (R):

(247) ##STR00263##
or a salt, stereoisomer, or isotopically labeled derivative thereof, wherein each P.sup.1 is independently hydrogen, optionally substituted alkyl, or an oxygen protecting group, and X, L.sup.X, L.sup.1a, L.sup.2a are as described herein, to provide a compound of Formula (S). In certain embodiments, the oxygen protecting group is silyl (e.g., TMS, TES, TIPS, TBDMS). In certain embodiments, the step of deprotecting is performed in the presence of an acid. In certain embodiments, the step of deprotecting is performed in the presence of a base. In certain embodiments, the step of deprotecting is performed in the presence of a reductant. In certain embodiments, the step of deprotecting is performed in the presence of a fluoride source (e.g., tetrabutylammonium fluoride (TBAF)).

(248) In another aspect, the method of preparing a compound of Formula (I) further comprises contacting a compound of Formula (Q):

(249) ##STR00264##
or a salt, stereoisomer, or isotopically labeled derivative thereof, wherein X is as described herein, with a compound of Formula (P):

(250) ##STR00265##
or a salt, stereoisomer, or isotopically labeled derivative thereof, wherein P.sup.1 is hydrogen, optionally substituted alkyl, or an oxygen protecting group, and L.sup.Xa is substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene, in the presence of a reductant, to provide a compound of Formula (R). In certain embodiments, the oxygen protecting group is silyl (e.g., TMS, TES, TIPS, TBDMS). In some embodiments, the step of esterifying is performed in the presence of a base. In some embodiments, the base is an organic base. In certain embodiments, the organic base is an aliphatic amine or aromatic amine. In certain embodiments, the organic base is a primary amine, secondary amine, or tertiary amine. In certain embodiments, the organic base is triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,6-lutidine, or 4-dimethylaminopyridine (DMAP). In certain embodiments, the reductant is a reductant described herein. In certain embodiments, the reductant is a borohydride or borane. In some embodiments, the reductant is sodium borohydride or sodium triacetoxyborohydride.

(251) The step(s) of the methods of preparing the compounds 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 compound described herein) or intermediate may be formed using the methods. A suitable condition may include the presence of a base. In certain embodiments, the base is an inorganic base. In certain embodiments, the inorganic base is an alkali metal carbonate (e.g., Li.sub.2CO.sub.3, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Rb.sub.2CO.sub.3, or Cs.sub.2CO.sub.3). In certain embodiments, the inorganic base is an alkali metal bicarbonate (e.g., LiHCO.sub.3, NaHCO.sub.3, KHCO.sub.3, RbHCO.sub.3, or CsHCO.sub.3). In certain embodiments, the inorganic base is an alkaline earth metal carbonate (e.g., BeCO.sub.3, MgCO.sub.3, CaCO.sub.3, SrCO.sub.3, or BaCO.sub.3). In certain embodiments, the inorganic base is an alkaline earth metal bicarbonate (e.g., Be(HCO.sub.3).sub.2, Mg(HCO.sub.3).sub.2, Ca(HCO.sub.3).sub.2, Sr(HCO.sub.3).sub.2, or Ba(HCO.sub.3).sub.2). In certain embodiments, the base is an organic base. In certain embodiments, the organic base is an aliphatic amine or aromatic amine. In certain embodiments, the organic base is a primary amine, secondary amine, or tertiary amine. In certain embodiments, the organic base is triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,6-lutidine, or 4-dimethylaminopyridine (DMAP). A base described herein may be present in a stoichiometric amount (e.g., at least 1 equivalent compared to the amount of a compound of Formula (B), (D), (F), (H), (Q), or (S)) or catalytic amount (e.g., less than 1 equivalent compared to the amount of a compound of Formula (B), (D), (F), (H), (Q), or (S)).

(252) A suitable condition may include the presence of a carbodiimide (e.g., N,N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or N,N′-diisopropylcarbodiimide (DIC)).

(253) A suitable condition may include the presence of a catalyst (e.g., DMAP, 1-hydroxybenzotriazole (HOBt), or 1-hydroxy-7-azabenzotriazole (HOAt)).

(254) 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.

(255) A suitable condition may also include a suitable temperature under which a step of a method of preparing a compound 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 at most about 100° C., at most about 80° C., at most about 60° C., at most about 40° C., at most about 23° C., or at most about 0° C. Combinations of the above-referenced ranges (e.g., at least about 23° C. and at most about 80° C.) are also within the scope of the disclosure. A suitable temperature may be a variable temperature (e.g., from 23° C. to about 80° C.) during a step of a method of preparing a compound described herein.

(256) A suitable condition may also include a suitable pressure under which a step of a method of preparing a compound described herein is performed. In certain embodiments, the suitable pressure is about 1 atmosphere.

(257) A suitable condition may also include a suitable atmosphere under which a step of a method of preparing a compound 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.

(258) A suitable condition may also include a suitable time duration that a step of a method of preparing a compound 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).

(259) One or more intermediates resulting from a step of a method of preparing the compounds 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 compound 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. In certain embodiments, an intended product described herein is substantially pure (e.g., substantially free of impurities) (e.g., at least about 90%, at least about 95%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.9%, or more pure) prior to or without purification.

(260) Another aspect of the present disclosure relates to compounds prepared by a method described herein (e.g., any one of Methods A to F). In certain embodiments, described herein are compounds prepared by a method described herein, wherein the alcohol of Formula (A) or (E) is a compound in Table 7, or a salt, stereoisomer, and isotopically labeled derivative thereof, and the carboxylic acid of Formula (B) or (F) is a compound in Table 8, or a salt, stereoisomer, and isotopically labeled derivative thereof.

(261) TABLE-US-00008 TABLE 7 Exemplary alcohols that are useful in preparing a compound of the disclosure embedded image 0

(262) TABLE-US-00009 TABLE 8 Exemplary carboxylic acids that are useful in preparing a compound of the disclosure embedded image 0 0 00 01 02 03 04 05 06 07
Compositions

(263) In another aspect, the present disclosure provides compositions comprising a compound described herein and optionally an excipient. In certain embodiments, a composition described herein comprises a compound 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 compound 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 compound 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 compound 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 compound described herein and a nutraceutically acceptable excipient.

(264) 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 compound 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.

(265) 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).

(266) 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.

(267) 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.

(268) 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 compound described herein. In some embodiments, the composition increases the delivery of the agent due to the presence of a complex formed between the compound and the agent. In some embodiments, the presence of a compound 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 compound 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 compound.

(269) 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.

(270) 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 an immunological 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 metabolic disorder. In certain embodiments, the compositions are useful for treating and/or preventing hepatic carcinoma, hypercholesterolemia, refractory anemia, or familial amyloid neuropathy.

(271) 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.

(272) 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.

(273) 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 compounds described herein may be combined with polymers (synthetic or natural), surfactants, substituted or unsubstituted cholesterols, steroids, 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.

(274) 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 compound 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.

(275) 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.

(276) 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.

(277) 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.

(278) 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.

(279) 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.

(280) 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.

(281) 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.

(282) 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.

(283) 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.

(284) 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.

(285) 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.

(286) 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.

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

(288) 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.

(289) 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.

(290) 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.

(291) 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.

(292) 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.

(293) 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.

(294) 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.

(295) 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.

(296) 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.

(297) 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.

(298) 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.

(299) 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.

(300) 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.

(301) 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.

(302) 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.

(303) 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.

(304) 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.

(305) 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.

(306) 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).

(307) 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.

(308) 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.

(309) 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.

(310) 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.

(311) 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.

(312) Compounds 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.

(313) 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).

(314) 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).

(315) 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.

(316) 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.

(317) 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.

(318) 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 substituted or unsubstituted cholesterol, a steroid, or a polyethylene glycol (PEG)-containing material). In certain embodiments, the lipid included in the compositions is a triglyceride, a driglyceride, a PEGylated lipid, dimyristoyl-PEG2000 (DMG-PEG2000), a phospholipid (e.g., 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)), dioleoylphosphatidylethanolamine (DOPE), a substituted or unsubstituted cholesterol, a steroid 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 substituted or unsubstituted cholesterol, a steroid, 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 substituted or unsubstituted cholesterol, a steroid, 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 substituted or unsubstituted cholesterol, a steroid, and an apolipoprotein. In certain embodiments, the compositions include a hydrophilic polymer, a phospholipid, a substituted or unsubstituted cholesterol, and a steroid. In certain embodiments, the compositions include PEG, DSPC, and cholesterol.

(319) 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.

(320) Agents

(321) Agents that are delivered by the systems (e.g., pharmaceutical compositions) described herein 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.

(322) 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, β-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.

(323) In certain embodiments, an agent described herein is a polynucleotide. In certain embodiments, the agent is a DNA. 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 an RNA. In certain embodiments, the agent is siRNA. In certain embodiments, the agent is 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 a pDNA, siRNA, or a combination thereof. In certain embodiments, the agent is a pDNA, siRNA, mRNA, or a combination thereof. 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, the agent is an siRNA. In certain embodiments, the agent is a dsRNA. In certain embodiments, the agent is an shRNA. In certain embodiments, the agent is an miRNA. miRNAs are genomically encoded non-coding RNAs of about 21-23 nucleotides in length that help regulate gene expression, particularly during development. See, e.g., Bartel, 2004, Cell, 116:281; Novina and Sharp, 2004, Nature, 430:161; and U.S. Patent Application Publication, US 2005/0059005; Wang et al., 2007, Front. Biosci., 12:3975; and Zhao, 2007, Trends Biochem. Sci., 32:189. In certain embodiments, the agent is an mRNA. In certain embodiments, the agent is a tRNA. In certain embodiments, the agent is an asRNA. In certain embodiments, the agent is a combination of pDNA and siRNA. 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.

(324) 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.

(325) The siRNA, dsRNA, shRNA, miRNA, mRNA, tRNA, asRNA, 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.

(326) 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.

(327) 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.

(328) 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, 0(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.

(329) 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.

(330) 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.

(331) 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.

(332) The antigenic protein or peptides encoded by the polynucleotide may be derived from bacterial organisms, such as Streptococccus 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.

(333) An agent described herein may be covalently or non-covalently (e.g., complexed or encapsulated) attached to a compound 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.

(334) 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.

(335) 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.

(336) Targeting Agents

(337) Since it is often desirable to target a particular cell, collection of cells, or tissue, compounds described herein, and the compositions, complexes, liposomes, micelles, and particles thereof, may be modified to include targeting moieties. For example, the compounds may include a targeting moiety. The targeting agent may be included throughout a particle of a compound 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, π-π stacking) interactions) the formed particle using standard chemical techniques.

(338) Complexes of a Lipidoid and an Agent

(339) The present disclosure contemplates that the compounds 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 compounds have several desirable properties that make a composition that includes the compound and an agent suitable for delivering the agent to a subject, tissue, or cell. The desirable properties include: 1) the ability of the compound to complex with and “protect” the agent that may otherwise be labile; 2) the ability of the compound to buffer the pH in an endosome of the cell; 3) the ability of the compound to act as a “proton sponge” and cause endosomolysis; and 4) the ability of the compound to substantially neutralize the negative charges of the agent.

(340) A compound and agent described herein may form a complex in a composition of the disclosure. For example, a compound 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 compound under conditions suitable to form a complex. In certain embodiments, the agent binds to the compound to form a complex through non-covalent interactions. In certain embodiments, the agent binds to the compound to form a complex through electrostatic interactions. Without wishing to be bound by any particular theory, one or more amino moieties of a compound 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 compound, or a composition thereof, is delivered to a subject, tissue, or cell (e.g., under physiological conditions). The agent may bind to the compound to form a complex through electrostatic interactions between the negative charges of the compound 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 ζ-potential. In certain embodiments the ζ-potential is between 0 and +30.

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

(342) A compound 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 compound 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 compounds described herein associated with an agent.

(343) The ratio of the amount of a compound described herein to the amount of an agent to be delivered in a described composition that includes the compound 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 compound 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 compound 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.

(344) The ratio of the amount of the amino moieties of a compound described herein to the amount of the phosphate moieties of a polynucleotide (i.e., nitrogen:phosphate ratio) in a described composition that includes the compound 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.

(345) Particles

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

(347) 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 (1-9). To date, several polymeric, lipid, and dendritic nanoparticles have been developed for the encapsulation and delivery of siRNAs (1, 3, 5, 7-15). 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 (10-17). Furthermore, high-throughput synthetic methods have been exploited for the accelerated discovery of potent lipid nanoparticles (LNPs) and evaluation of structure activity relationships (SARs) (16-20). 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.

(348) In certain embodiments, a compound described herein (e.g., a plurality of molecules of the compound) is in the form of a particle. In certain embodiments, a complex of a compound 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 μm, less than about 30 μm less than about 10 μm, less than about 3 μm, less than about 1 μm, 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 μm, at least about 3 μm, at least about 10 μm, at least about 30 μm, at least about 100 μm, at least about 300 μm, or at least about 1 mm. Combinations of the above ranges (e.g., at least about 100 nm and less than about 1 km) are also within the scope of the present disclosure.

(349) 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 substituted or unsubstituted cholesterol, a steroid, 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.

(350) 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.

(351) 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.

(352) 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).

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

(354) Micelles, Liposomes, and Lipoplexes

(355) A composition including a compound and agent described herein may be in the form of a micelle or liposome. In certain embodiments, the compound 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.

(356) 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 compound described herein for hydration, hydrating the compound with agitation, and sizing the vesicles to achieve a homogenous distribution of liposomes. A compound 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 compound 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 compound further complexes an agent, such as a polynucleotide.

(357) 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 Structure—Activity 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.

(358) Kits

(359) Also described herein are kits (e.g., packs). The kits provided may comprise a compound 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 compound or composition described herein. In some embodiments, the compound or composition provided in the first container and the compound or composition provided in the second container are combined to form one unit dosage form.

(360) 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.

(361) In certain embodiments, the described kits further include instructions for administering a compound 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.

(362) Methods of Treatment and Uses

(363) 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.

(364) 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.

(365) 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 compound described herein.

(366) In another aspect, the present disclosure provides methods of treating a disease described herein in a subject in need thereof. In certain embodiments, the present disclosure provides methods of preventing a disease described herein in a subject in need thereof. In certain embodiments, the disease is treated by the methods. In certain embodiments, a symptom of the disease is reduced or eliminated by the methods. In certain embodiments, the progression of the disease is slowed by the methods. In certain embodiments, the disease is prevented by the methods. In certain embodiments, the onset of the disease is delayed by the methods.

(367) In another aspect, the present disclosure provides methods of reducing the risk of developing a disease described herein in a subject in need thereof. In certain embodiments, the risk of developing the disease is reduced by the methods.

(368) In certain embodiments, a disease described herein is a genetic disease. In certain embodiments, the genetic disease is a genetic disease described herein. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is a cancer described herein. In certain embodiments, the disease is a benign neoplasm. In certain embodiments, the benign neoplasm is a benign neoplasm described herein. In certain embodiments, the disease is pathological angiogenesis. In certain embodiments, the pathological angiogenesis is pathological angiogenesis described herein. 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 an immunological 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 painful condition. In certain embodiments, the painful condition is a painful condition described herein. In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition (e.g., inflammatory pain) 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 metabolic disorder. In certain embodiments, the disease is hepatic carcinoma. In certain embodiments, the disease is hypercholesterolemia. In certain embodiments, the disease is refractory anemia. In certain embodiments, the disease is familial amyloid neuropathy.

(369) 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.

(370) 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.

(371) 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.

(372) 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.

(373) 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.

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

(375) Another aspect of the present disclosure relates to methods of screening a library of compounds to identify a compound that is useful in the methods described herein. In certain embodiments, the methods of screening a library of compounds are useful in identifying a compound 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 compound identified is useful for delivering an agent described herein to a subject, tissue, or cell. In certain embodiments, the compound identified is useful for treating and/or preventing a disease described herein. In certain embodiments, the library of compounds is a library of compounds described herein. In certain embodiments, the methods of screening a library include providing at least two different compounds described herein; and performing at least one assay using the compounds. In certain embodiments, at least one assay is useful in identifying a compound 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.

EXAMPLES

(376) 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 compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1. Preparation of the Compounds

(377) The compounds provided herein can be prepared from readily available starting materials using the following general methods (e.g., the method shown in Scheme E1, E2, or E3).

(378) It will be appreciated that where typical or preferred process conditions (e.g., reaction temperatures, times, mole ratios of reactants, solvents, and pressures) 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.

(379) Proton nuclear magnetic resonance (.sup.1H NMR) spectra were recorded with a Varian INOVA-500 spectrometer and are reported in parts per million (ppm) on the δ scale, and are referenced from the residual protium in the NMR solvent (CDCl.sub.3: δ 7.26 (CHCl.sub.3).

Example 1.1. Preparation of the Compounds by Esterification

(380) Compounds described herein (e.g., compounds of Formula (I) or (II)) may be prepared by esterification reactions (see, e.g., Neises et al., Angew. Chem. Int. Ed. 1978, 17, 522), such as the ones illustrated in Scheme 4.

(381) ##STR00308##

(382) In an exemplary synthesis, an alcohol of Formula (A) or (E) (1 equivalent) was dissolved in a solvent (e.g., dichloromethane, in which the concentration of the alcohol of Formula (A) or (E) was about 0.1 M). To this solution was added a carbodiimide (e.g., EDC (about 2a equivalents, where a is the number of hydroxyl moieties of a molecule of the alcohol of Formula (A)), a catalyst (e.g., HOBt (about 2a equivalents), and a carboxylic acid of Formula (B) or (F) (about 2a equivalents). A base (e.g., triethylamine (about 6a equivalents) was then added dropwise to the resulting mixture. The reaction mixture was stirred at room temperature for about 24 hours. Liquid chromatography/mass spectrometry was used to assess if the reaction was complete, and if it was not, additional amounts (e.g., 1 to 6a equivalents) of the carbodiimide, catalyst, carboxylic acid of Formula (B) or (F), and/or base were added so that the conversion of the alcohol of Formula (A) or (E) was close to 100% (e.g., at least about 90% or at least about 95%). Upon completion, the reaction mixture was diluted with the solvent (e.g., dichloromethane) and washed with an aqueous solution of 1 N hydrochloric acid, an aqueous solution of saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered through cotton, and concentrated under reduced pressure. .sup.1H NMR spectroscopy was used to assess the purity of the crude product. If the crude product included impurities, the crude product was purified via silica gel chromatography eluted with a 2% to 100% gradient of dichloromethane/ULTRA (where ULTRA is a solution consisting of 75% dichloromethane, 22% methanol, and 3% concentrated ammonium hydroxide) to yield the desired product. For example, compounds 24C18Oleic, 24C18Linoleic3, and 50C18Linoleic3 were prepared, and the .sup.1H NMR (CDCl.sub.3) spectra of these compounds are shown in FIGS. 4A to 4C, respectively.

Example 1.2. Preparation of the Compounds by Alkylation

(383) Compounds described herein (e.g., compounds of Formula (I) or (II)) may be prepared by alkylation reactions, such as the ones illustrated in Scheme 5.

(384) ##STR00309##

(385) In an exemplary synthesis, an amine of Formula (C) or (G) (1 equivalent) was dissolved in a solvent (e.g., DMF). A base (e.g., solid sodium carbonate (about 4b equivalents, where b is the number of amino protons of a molecule of the amine of Formula (C) or (G)) was added, followed by the addition of a compound of Formula (D) or (H) (about 2b equivalents). The resulting mixture was stirred vigorously at elevated temperature (e.g., about 50° C. or higher) for about 48 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluted with a 2% to 100% gradient of dichloromethane/ULTRA to yield the desired product.

Example 1.3. Preparation of the Compounds by Reductive Amination

(386) Compounds described herein (e.g., compounds of Formula (I) or (II)) may be prepared by reductive amination reactions, such as the ones illustrated in Scheme E3.

(387) ##STR00310##

(388) In an exemplary synthesis, an amine of Formula (C) or (G) (1 equivalent) was dissolved in a solvent (e.g., THF, in which the concentration of the amine of Formula (C) or (G) was about 0.1 M). An aldehyde of Formula (K) or (J) (about 3c equivalents, where c is the number of amino moieties of a molecule of the amine of Formula (C) or (G)) was added to the resulting mixture, followed by the addition of a reductant (e.g., sodium triacetoxy borohydride (about 2.7c equivalents)). The reaction mixture was stirred at room temperature for about 24 hours. Liquid chromatography/mass spectrometry was used to assess the conversion of the reaction, and more amounts (e.g., 1 to 3c equivalents) of the aldehyde of Formula (K) or (J) and the reductant were added to attempt to so that the conversion of the amine of Formula (C) or (G) was close to 100% (e.g., at least about 90% or at least about 95%). After completion, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluted with a 2% to 100% gradient of dichloromethane/ULTRA to yield the desired product.

Example 1.4.1. Nomenclature and Synthetic Considerations

(389) The following nomenclature system is one means of identifying the compounds of the invention. The nomenclature structure is in a general format as follows: AA-BB-CC-DD, wherein: AA refers to the specific core, e.g., core 50, which refers to a bis-lysine diketopiperazine based core. BB refers to the number of carbons between the lysine nitrogens and the alcohol oxygen. CC refers to the tail length of the fatty acid used for esterification, and, in cases wherein multiple tails exist with the same tail length, the specific tail name is used. DD refers to the total number of tails off of the diketopiperazine core.

Example 1.4.2. Reductive Amination Protocol for the 50-C2-CC-DD, 50-C4-CC-DD, and 50-C5-CC-DD Cores

(390) To the bis-lysine diketopiperazine core (1 equiv.) in THF was added NEt.sub.3 (2.2 equiv.). The reaction mixture was stirred for 30 minutes, until the solid was nearly fully dissolved, and then to it was added the aldehyde (6.9 equiv.), followed by NaB(OAc).sub.3H (5 equiv.). The solution was stirred overnight. It was then diluted in EtOAc, washed with brine, filtered over Na.sub.2SO.sub.4, and concentrated in vacuo to yield the product. The crude product mixtures were purified using silica gel chromatography eluting with a gradient of dichloromethane to dichloromethane:methanol:ammonium hydroxide (75%:22%:3% v:v:v).

(391) 50-C2-CC-DD Core

(392) ##STR00311##

(393) To the bis-lysine diketopiperazine core (1.000 g, 2.66 mmol, 1 equiv.) in THF (88 ml) was added NEt.sub.3 (823 al, 5.90 mmol, 2.2 equiv.). The reaction mixture was stirred for 1.5 h, until the solid was nearly fully dissolved, and then to it was added the C2 protected aldehyde (3.49 ml, 18.3 mmol, 6.9 equiv.), followed by NaB(OAc).sub.3H (2.814 g, 13.3 mmol, 5 equiv.). The solution was stirred overnight. It was then diluted in EtOAc, washed with brine, filtered over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product mixture was purified using silica gel chromatography eluting with a 0.fwdarw.100% gradient of dichlormethane/methanol/ammonium hydroxide (75%/22%/3% v/v/v):dichloromethane. Fractions were concentrated under reduced pressure to afford the desired products in 58% yield. .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): 6.15 (br, 2H, NH), 3.99 (br, 2H, COCHN), 3.8 (t, 8H, NCH.sub.2CH.sub.2OSi), 2.65 (t, 8H, NCH.sub.2CH.sub.2OSi), 2.55 (t, 4H, NCH.sub.2), 1.99 (m, 2H, COCHCH.sub.2), 1.8 (m, 2H, COCHCH.sub.2), 1.45 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.40 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 0.89 (s, 36H, OSi(CH.sub.3).sub.2C(CH.sub.3).sub.3), 0.04 (s, 36H, OSi(CH.sub.3).sub.2C(CH.sub.3).sub.3).

(394) 50-C4-CC-DD Core

(395) ##STR00312##

(396) To the bis-lysine diketopiperazine core (373 mg, 0.99 mmol, 1 equiv.) in THF (33 ml) was added NEt.sub.3 (307 μl, 2.18 mmol, 2.2 equiv). The reaction mixture was stirred for 30 minutes, until the solid was nearly fully dissolved, and then to it was added the C4 protected aldehyde (1.382 g, 6.83 mmol, 6.9 equiv.), followed by NaB(OAc).sub.3H (1.05 g, 4.95 mmol, 5 equiv.). The solution was stirred overnight. It was then diluted in EtOAc, washed with brine, filtered over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product mixture was purified using silica gel chromatography eluting with a 0.fwdarw.100% gradient of dichlormethane/methanol/ammonium hydroxide (75%/22%/3% v/v/v):dichloromethane. Fractions were concentrated under reduced pressure to afford the desired products in 41% yield. .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): 6.4 (br, 2H, NH), 3.95 (br, 2H, COCHN), 3.62 (t, 8H, CH.sub.2OSi), 2.40 (m, 12H, NCH.sub.2), 1.98 (m, 4H, COCHCH.sub.2), 1.33-1.84 (m, 24H, CH.sub.2), 0.89 (s, 36H, OSi(CH.sub.3).sub.2C(CH.sub.3).sub.3), 0.04 (s, 24H, OSi(CH.sub.3).sub.2C(CH.sub.3).sub.3).

(397) 50-C5-CC-DD Core:

(398) ##STR00313##

(399) To the bis-lysine diketopiperazine core (373 mg, 0.99 mmol, 1 equiv.) in THF (33 ml) was added NEt.sub.3 (307 μl, 2.18 mmol, 2.2 equiv.). The reaction mixture was stirred for 30 minutes, until the solid was nearly fully dissolved, and then to it was added the protected aldehyde (1.477 g, 6.83 mmol, 6.9 equiv.), followed by NaB(OAc).sub.3H (1.050 g, 4.95 mmol, 5 equiv.). The solution was stirred overnight. It was then diluted in EtOAc, washed with brine, filtered over Na.sub.2SO.sub.4, and concentrated under reduced pressure. The crude product mixture was purified using silica gel chromatography eluting with a 0.fwdarw.100% gradient of dichlormethane/methanol/ammonium hydroxide (75%/22%/3% v/v/v):dichloromethane. Fractions were concentrated under reduced pressure to afford the desired products in 19% yield. .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): 6.17 (br, 2H, NH), 3.97 (br, 2H, COCHN), 3.59 (t, 8H, CH.sub.2OSi), 2.39 (m, 12H, NCH.sub.2), 1.24-1.99 (m, 36H, CH.sub.2), 0.89 (s, 36H, OSi(CH.sub.3).sub.2C(CH.sub.3).sub.3), 0.04 (s, 24H, OSi(CH.sub.3).sub.2C(CH.sub.3).sub.3).

Example 1.4.3. Alkylation Protocol for the 50-C3-CC-DD Core

(400) 50-C3-CC-DD Core.

(401) ##STR00314##

(402) To the bis-lysine diketopiperazine core (263.4 mg, 0.7 mmol, 1 equiv.) in DMF (10 ml) was added NEt.sub.3 (1.32 ml, 9.45 mmol, 13.5 equiv.). The mixture was stirred at room temperature for 15 minutes. To the flask was then added (3-bromopropoxy)(tert-butyl)dimethylsilane (1.297 ml, 5.6 mmol, 8 equiv.), and the reaction was stirred at 50° C. for 18 hours. The mixture was diluted in ethyl acetate, washed with brine, filtered through Na.sub.2SO.sub.4, and concentrated under reduced pressure. The crude product mixture was purified using silica gel chromatography eluting with a 0.fwdarw.100% gradient of dichlormethane/methanol/ammonium hydroxide (75%/22%/3% v/v/v):dichloromethane. Fractions were concentrated under reduced pressure to afford the desired products in 13% yield. .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): 6.5 (br, 2H, NH), 3.93 (br, 2H, COCHN), 3.58 (t, 8H, NCH.sub.2CH.sub.2CH.sub.2OSi), 2.49 (t, 8H, NCH.sub.2CH.sub.2CH.sub.2OSi), 2.40 (t, 4H, NCH.sub.2), 1.97 (m, 2H, COCHCH.sub.2), 1.75 (m, 2H, COCHCH.sub.2), 1.64 (quintet, 8H, NCH.sub.2CH.sub.2CH.sub.2OSi), 1.48 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.42 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 0.89 (s, 36H, OSi(CH.sub.3).sub.2C(CH.sub.3).sub.3), 0.04 (s, 36H, OSi(CH.sub.3).sub.2C(CH.sub.3).sub.3).

Example 1.4.4. Desilylation-Esterification Protocol

(403) To the protected alcohols (0.088 mmol, 1 equiv.) in THF (6 ml) was added TBAF (1.75 ml, IM in THF, 1.75 mmol, 12 equiv.). The solution was stirred for one hour and the reaction was then quenched with 1 drop of H.sub.2O.

(404) To a solution of the deprotected alcohol in CH.sub.2Cl.sub.2 (6 ml) was added HOBt (120.7 mg, 0.88 mmol, 10 equiv.), EDC (168.7 mg, 0.88 mmol, 10 equiv.), a carboxylic acid (0.88 mmol, 10 equiv.), and then NEt.sub.3 (178 al, 2.2 mmol, 25 equiv.). The reaction was stirred overnight, and was then diluted with ethyl acetate. The organic phase was washed with 1 N HCl, with saturated sodium bicarbonate, and then with brine. The organic phase was dried over sodium sulfate, was filtered through cotton, and was concentrated under reduced pressure. The crude product mixture was purified using silica gel chromatography eluting with a 0.fwdarw.100% gradient of dichlormethane/methanol/ammonium hydroxide (75%/22%/3% v/v/v):dichloromethane. Fractions were concentrated under reduced pressure to afford the desired products in moderate yield.

(405) 50-C2-C9-4Tail

(406) ##STR00315##

(407) C9 refers to nonanoic acid. 1H NMR (500 MHz, CDCl.sub.3, ppm): 6.15 (br, 2H, NH), 4.1 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.99 (br, 2H, COCHN), 2.73 (t, 8H, OCOCH.sub.2), 2.53 (t, 4H, NCH.sub.2), 2.29 (t, 8H, NCH.sub.2CH.sub.2OCO), 1.96 (m, 2H, COCHCH.sub.2), 1.78 (m, 2H, COCHCH.sub.2), 1.61 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.77 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.1-1.35 (m, 48H, CH.sub.2), 0.88 (t, 12H, CH.sub.3).

(408) 50-C2-C12-4Tail

(409) ##STR00316##

(410) C12 refers to dodecanoic acid. .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): 6.12 (br, 2H, NH), 4.11 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.97 (br, 2H, COCHN), 2.75 (t, 8H, OCOCH.sub.2), 2.54 (t, 4H, NCH.sub.2), 2.29 (t, 8H, NCH.sub.2CH.sub.2OCO), 1.97 (m, 2H, COCHCH.sub.2), 1.77 (m, 2H, COCHCH.sub.2), 1.61 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.45 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.1-1.17 (m, 72H, CH.sub.2), 0.9 (t, 12H, CH.sub.3).

(411) 50-C2-C15-4Tail

(412) ##STR00317##

(413) C15 refers to pentadecanoic acid. .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): 6.17 (br, 2H, NH), 4.11 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.97 (br, 2H, COCHN), 2.74 (t, 8H, OCOCH.sub.2), 2.53 (t, 4H, NCH.sub.2), 2.29 (t, 8H, NCH.sub.2CH.sub.2OCO), 1.97 (m, 2H, COCHCH.sub.2), 1.76 (m, 2H, COCHCH.sub.2), 1.59 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.45 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.17-1.34 (m, 96H, CH.sub.2), 0.9 (t, 12H, CH.sub.3).

(414) 50-C2-C18oleic-4Tail

(415) ##STR00318##

(416) C18oleic refers to oleic acid. 1H NMR (500 MHz, CDCl.sub.3, ppm): 6.13 (br, 2H, NH), 5.34 (m, 8H, CH.sub.2CHCHCH.sub.2), 4.11 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.98 (br, 2H, COCHN), 2.74 (t, 8H, OCOCH.sub.2), 2.53 (t, 4H, NCH.sub.2), 2.29 (t, 8H, NCH.sub.2CH.sub.2OCO), 2.00 (m, 16H, CH.sub.2CHCHCH.sub.2), 1.94 (m, 2H, COCHCH.sub.2), 1.77 (m, 2H, COCHCH.sub.2), 1.61 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.45 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.21-1.36 (m, 88H, CH.sub.2), 0.9 (t, 12H, CH.sub.3).

(417) 50-C2-C18elaidic-4Tail

(418) ##STR00319##

(419) C18elaidic refers to elaidic acid. 1H NMR (500 MHz, CDCl.sub.3, ppm): 6.13 (br, 2H, NH), 5.39 (m, 8H, CH.sub.2CHCHCH.sub.2), 4.10 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.97 (br, 2H, COCHN), 2.74 (t, 8H, OCOCH.sub.2), 2.52 (t, 4H, NCH.sub.2), 2.27 (t, 8H, NCH.sub.2CH.sub.2OCO), 1.95 (m, 16H, CH.sub.2CHCHCH.sub.2), 1.78 (m, 2H, COCHCH.sub.2), 1.69 (m, 2H, COCHCH.sub.2), 1.60 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.45 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.20-1.37 (m, 88H, CH.sub.2), 0.87 (t, 12H, CH.sub.3).

(420) 50-C2-C18lin2-4Tail

(421) ##STR00320##

(422) C18lin2 refers to linoleic acid. 1H NMR (500 MHz, DMSO-d.sub.6, ppm): 6.13 (br, 2H, NH), 5.34 (m, 16H, CH.sub.2CHCHCH.sub.2), 4.11 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.98 (br, 2H, COCHN), 2.74 (t, 8H, OCOCH.sub.2), 2.53 (t, 8H, NCH.sub.2CH.sub.2OCO), 2.29 (t, 4H, NCH.sub.2), 2.00 (m, 16H, CH.sub.2CHCHCH.sub.2CHCHCH.sub.2), 1.94 (m, 2H, COCHCH.sub.2), 1.77 (m, 2H, COCHCH.sub.2), 1.61 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.45 (m, 4H, NCH.sub.2CH.sub.2CH.sub.2CH.sub.2), 1.21-1.36 (m, 88H, CH.sub.2), 0.9 (t, 12H, CH.sub.3).

(423) 50-C3-C18Lin2-4Tail

(424) ##STR00321##

(425) C18lin2 refers to linoleic acid. H NMR (500 MHz, CDCl.sub.3, ppm): 6.27 (br, 2H, NH), 5.34 (m, 16H, CH.sub.2CHCHCH.sub.2), 4.09 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.97 (br, 2H, COCHN), 2.76 (t, 8H, OCOCH.sub.2), 2.26-2.57 (t, 12H, NCH.sub.2), 2.22 (m, 8H, CHCH.sub.2CH, 2.04 (m, 16H, CH.sub.2CHCHCH.sub.2CHCHCH.sub.2), 1.14-1.85 (m, 84H, CH.sub.2), 0.9 (t, 12H, CH.sub.3).

(426) 50-C4-C7-4Tail

(427) ##STR00322##

(428) C7 refers to heptanoic acid. .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): 6.15 (br, 2H, NH), 4.07 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.97 (br, 2H, COCHN), 2.43 (br, 12H, NCH.sub.2), 2.30 (t, 8H, t, 8H, OCOCH.sub.2), 1.96 (m, 2H, COCHCH.sub.2), 1.76 (m, 2H, COCHCH.sub.2), 1.1-1.67 (m, 64H, CH.sub.2), 0.9 (t, 12H, CH.sub.3).

(429) 50-C4-C10-4Tail

(430) ##STR00323##

(431) C10 refers to decanoic acid. .sup.1H NMR (500 MHz, CDCl.sub.3, ppm): 6.23 (br, 2H, NH), 4.07 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.97 (br, 2H, COCHN), 2.40 (br, 12H, NCH.sub.2), 2.30 (t, 8H, t, 8H, OCOCH.sub.2), 1.97 (m, 2H, COCHCH.sub.2), 1.77 (m, 2H, COCHCH.sub.2), 1.14-1.69 (m, 80H, CH.sub.2), 0.88 (t, 12H, CH.sub.3).

(432) 50-C4-C13-Tail

(433) ##STR00324##

(434) C13 refers to tridecanoic acid. 1H NMR (500 MHz, CDCl.sub.3, ppm): 6.25 (br, 2H, NH), 4.07 (m, 8H, NCH.sub.2CH.sub.2OCO), 3.96 (br, 2H, COCHN), 2.39 (br, 12H, NCH.sub.2), 2.29 (t, 8H, t, 8H, OCOCH.sub.2), 1.96 (m, 2H, COCHCH.sub.2), 1.75 (m, 2H, COCHCH.sub.2), 1.13-1.68 (m, 104H, CH.sub.2), 0.88 (t, 12H, CH.sub.3).

(435) 50-C4-C18oleic-4Tail

(436) ##STR00325##

(437) C18oleic refers to oleic acid. 1H NMR (500 MHz, CDCl.sub.3, ppm): 6.22 (br, 2H, NH), 5.35 (m, 8H, CH.sub.2CHCHCH.sub.2), 4.07 (m, 8H, CH.sub.2CH.sub.2OCO), 3.98 (br, 2H, COCHN), 2.39 (br, 12H, NCH.sub.2), 2.29 (t, 8H, OCOCH.sub.2), 2.04 (m, 16H, CH.sub.2CHCH), 1.96 (m, 2H, COCHCH.sub.2), 1.77 (m, 2H, COCHCH.sub.2), 1.18-1.70 (m, 110H, CH.sub.2), 0.88 (t, 12H, CH.sub.3).

(438) 50-C4-C18lin2-4Tail

(439) ##STR00326##

(440) C18lin2 refers to linoleic acid. 1H NMR (500 MHz, CDCl.sub.3, ppm): 6.29 (br, 2H, NH), 5.35 (m, 16H, CH.sub.2CHCHCH.sub.2), 4.07 (m, 8H, CH.sub.2CH.sub.2OCO), 3.96 (br, 2H, COCHN), 2.77 (t, 8H, OCOCH.sub.2), 2.44 (br, 12H, NCH.sub.2), 2.29 (t, 8H, CHCH.sub.2CH), 2.04 (m, 16H, CH.sub.2CHCHCH.sub.2CHCHCH.sub.2), 1.96 (m, 2H, COCHCH.sub.2), 1.77 (m, 2H, COCHCH.sub.2), 1.22-1.68 (m, 88H, CH.sub.2), 0.88 (t, 12H, CH.sub.3).

Example 2. Biological Assays of the Compounds

(441) In addition to the polyamine-fatty acid derived lipidoids (e.g., compounds of Formula (I) or (II), helper lipids were used to generate the liposomal nanoparticles: cholesterol, dimyristoyl-PEG2000 (DMG-PEG2000), distearoylphosphatidylcholine (DSPC), and dioleoylphosphatidylethanolamine (DOPE). The lipids (e.g., the lipidoids and helper lipids) were solubilized in ethanol and combined. The RNA (e.g., mRNA) was dissolved in water and then added to a citric acid buffer (pH 3.0). Two methods (Methods (a) and (b)) were used to formulate the liposomal nanoparticles, with both methods requiring the use of syringe pumps and a microfluidics device (Chen et al., J. Am. Chem. Soc. 2012, 134, 6948-6951). In Method (a), the lipid and RNA solutions were pumped into the microfluidics device in a 1:1 ratio at 300 μl/minute, followed by addition of PBS at 600 μL/minute. In Method (b), the RNA and lipids were pumped in at a ratio of 3:1 at 900 μL/minute and 300 μL/minute, respectively. After formulating, the liposomal nanoparticles are dialyzed in 20 k MW cutoff dialysis cassettes against PBS for 2 hours. Entrapment and mRNA concentration were determined via RIBOGREEN assay; particle size was determined using a ZETASIZER (Malvern).

(442) Exemplary lipidoids (e.g., compounds of Formula (I) or (II)) of the disclosure were examined for efficacy in vitro. HeLa cells were transfected with 10 ng of formulated luciferase mRNA, and examined for luminescence 24 hours later. Exemplary results are shown in FIG. 3.

(443) Mice were injected with formulated luciferase mRNA using the compound 24C18Oleic at a dose of 1 mg/kh mRNA; after 6 hours, the murine organs were examined ex vivo, and luminescence was successfully seen in the spleen of the treated mice (FIG. 1). The EPO levels of mice were examined 6 hours after treatment with formulated human EPO mRNA at a dose of 1 mg/kg. Several lipidoids (e.g., compounds 24C18Oleic, 24C18Linoleic2, and 24C18Linoleic3) were examined, resulting in EPO levels ranging from 25 ng/mL to over 75 ng/mL (FIG. 2).

EQUIVALENTS AND SCOPE

(444) 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.

(445) 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 described herein, is/are referred to as comprising particular elements and/or features, certain embodiments described herein or aspects described herein 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 described herein, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

(446) 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 described herein can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

(447) 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.

Polyamine-fatty acid derived lipidoids and uses thereof

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C07D241/08

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C07C219/06

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A61K31/495

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Abstract

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