Polymers, hydrogels, and uses thereof

Abstract

Described herein are polymers, polymeric gels, or a composition thereof, for drug delivery. The polymers, which include boronic-acid containing moieties (e.g., ##STR00001##
and polyol-containing moieties (e.g., ##STR00002##
are prepared by free-radical polymerization and can self-assemble into polymeric gels such as hydrogels. Also provided are methods or preparing the polymers, kits involving the polymers and/or polymeric gels or a composition thereof, for use as materials or delivery applications of an agent to a subject.

Claims

1. A polymer of Formula (I): ##STR00096## or a salt thereof, wherein: X.sup.A is 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.sup.XA, N(R.sup.XA).sub.2, C(NR.sup.XA)R.sup.XA, C(NR.sup.XA)OR.sup.XA, C(NR.sup.XA)N(R.sup.XA).sub.2, C(O)R.sup.XA, C(O)OR.sup.XA, or C(O)N(R.sup.XA).sub.2, wherein each instance of R.sup.XA is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.XA are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; t is 10 to 2000; and each instance of R is independently a side chain selected from: boronic acid-containing moieties of Formula (a): ##STR00097## wherein: each instance of R.sup.AA is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2; each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring; k is 0, 1, 2, 3, or 4; L.sup.A is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LA, or C(O), wherein each instance of R.sup.LA is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; and polyol-containing moieties of Formula (c): ##STR00098## wherein: X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)R.sup.a, C(O)OR.sup.a, or C(O)N(R.sup.a).sub.2; m is an integer between 1 and 10, inclusive; L.sup.C is a substituted or unsubstituted, C.sub.1-10 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O), wherein each instance of R.sup.LB is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; and amine-containing moieties of Formula (b): ##STR00099## wherein: R.sup.N is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl; R.sup.NPG is a nitrogen protecting group; and L.sup.B is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O), wherein each instance of R.sup.LB is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; and aliphatic moieties of Formula (d): ##STR00100## wherein: L.sup.D is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LD, or C(O), wherein R.sup.LD is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; and R.sup.D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.D2, or NR.sup.D2.sub.2, wherein R.sup.D2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, optionally wherein one or more chain atoms of an alkyl chain are independently replaced with alkenyl, O, NR.sup.LD, or C(O); provided that the polymer contains at least one boronic acid-containing moiety of Formula (a) and at least on polyol-containing moiety of Formula (c).

2. A composition comprising a polymer of claim 1 and optionally an excipient.

3. The composition of claim 2, wherein the excipient is a pharmaceutically acceptable excipient.

4. The composition of claim 2, further comprising an agent.

5. The composition of claim 4, wherein the agent is a polynucleotide, small molecule, peptide, protein, or cell.

6. The composition of claim 5, wherein the agent is a polynucleotide and the polynucleotide is DNA.

7. The composition of claim 6, wherein the DNA is single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA, satellite DNA, or viral DNA.

8. The composition of claim 5, wherein the agent is a polynucleotide and the polynucleotide is RNA.

9. The composition of claim 8, wherein the RNA is small interfering RNA (siRNA).

10. The composition of claim 8, wherein the RNA is messenger RNA (mRNA).

11. The composition of claim 8, wherein the RNA 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.

12. The composition of claim 5, wherein the agent is a polynucleotide and the polynucleotide encodes a protein or peptide.

13. The composition of claim 2, further comprising a lipid.

14. The composition of claim 2, wherein the composition is a gel.

15. The composition of claim 2, wherein the composition is a hydrogel.

16. The polymer of claim 1, wherein the two instances of X.sup.A are the same.

17. The polymer of claim 1, wherein the two instances of X.sup.A are different.

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

19. The polymer of claim 1, wherein at least one instance of X.sup.A is C(O)N(R.sup.XA).sub.2.

20. The polymer of claim 1, wherein at least one instance of X.sup.A is hydrogen.

21. The polymer of claim 1, wherein the boronic acid-containing moieties of Formula (a) are independently of the formula: ##STR00101## wherein n is 0, 1, 2, 3, 4, 5, or 6.

22. The polymer of claim 1, wherein the amine-containing moieties of Formula (b) are independently of the formula: ##STR00102## wherein L.sup.B1 is a substituted or unsubstituted, C.sub.1-4 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O).

23. The polymer of claim 1, wherein the polyol-containing moietis of Formula (c) are independently of the formula: ##STR00103## wherein L.sup.C1 is a substituted or unsubstituted, C.sub.1-8 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O).

24. The polymer of claim 1, wherein the aliphatic moieties of Formula (d) are independently of the formula: ##STR00104## wherein R.sup.D1 is substituted or unsubstituted alkyl.

25. The polymer of claim 1 comprising a plurality of side chains selected from: ##STR00105##

26. The polymer of claim 1, comprising a plurality of side chains selected from: ##STR00106##

27. The polymer of claim 1, wherein t is between 10 and 1000, inclusive.

28. The polymer of claim 1, wherein t is between 10 and 100, inclusive.

Description

BRIEF DESCRIPTION OF THE FIGURE

(1) The FIGURE shows that the frequency dependence of the storage and loss oscillatory shear moduli (G and G, respectively) of the self-assembled polymers is consistent with hydrogel-like behavior, as the G and G curves are linear and parallel with G is dominant across the whole range of frequencies studied.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

(2) The present invention relates to polymers, methods of preparing such polymers by free radical polymerization, compositions comprising the polymer, and methods of using the polymers. The polymers are of Formula (I):

(3) ##STR00013##
comprising a plurality of side chains (R) and a polyethylene backbone. X.sup.A and t are defined herein, and each instance of R is independently a side chain selected from boronic acid-containing moieties (e.g.,

(4) ##STR00014##
polyol-containing moieties (e.g.,

(5) ##STR00015##
amine-containing moieties (e.g.,

(6) ##STR00016##
and/or aliphatic moieties (e.g.,

(7) ##STR00017##
The boronic acid-containing moieties are derived from boronic acid-monomers of Formula (A) which are described herein. The general and specific embodiments for L.sup.A (including any variables therein), R.sup.AA (including any variables therein), and k recited for boronic acid-monomers of Formula (A) are applicable to L.sup.A, R.sup.AA, and K of the boronic acid-containing moieties. The amine-containing moieties are derived from amine-containing monomers of Formula (B), which are described herein. The general and specific embodiments for R.sup.N, R.sup.NPG, and L.sup.B, and including any variables therein recited for amine-containing monomers of Formula (B) are applicable to R.sup.N, R.sup.NPG, and L.sup.B, and including any variables therein recited of the amine-containing moieties. The polyol-containing moieties are derived from polyol-containing monomers of Formula (C), which are described herein. The general and specific embodiments for X, m, R, L.sup.C, and including any variables therein recited for polyol acid-monomers of Formula (C) are applicable to X, m, L.sup.C of the polyol-containing moieties. The aliphatic moieties are derived from aliphatic monomers of Formula (D), which are described herein. The general and specific embodiments for L.sup.D, R.sup.D1, and including any variables therein recited for polyol acid-monomers of Formula (D) are applicable to X, m, L.sup.C of the aliphatic moieties.

(8) In certain embodiments, the polymers include a side chain selected from boronic acid-containing moieties, polyol-containing moieties, and aliphatic moieties. In certain embodiments, the polymers include a side chain selected from boronic acid-containing moieties, amine-containing moieties, and aliphatic moieties. In certain embodiments, the polymers include a side chain selected from boronic acid-containing moieties, amine-containing moieties, polyol-containing moieties, and aliphatic moieties. In certain embodiments, the polymers include a side chain selected from boronic acid-containing moieties, amine-containing moieties, and polyol-containing moieties. In certain embodiments, the polymers include a side chain selected from boronic acid-containing moieties and amine-containing moieties. In certain embodiments, the polymers include a side chain selected from boronic acid-containing moieties and polyol-containing moieties.

(9) The polymers are able to form polymeric gels, such as hydrogels, in the presence of aqueous media (e.g., water based media) or other solvents (e.g., methanol or ethanol). The resulting polymer-based gels are useful as materials or for delivering various agents (e.g., polynucleotides, proteins, small molecules, peptides, antigen, drugs, cells, etc.) to a subject or to target cells, tissues, or organs within a subject. Also provided are compositions including cosmetic and pharmaceutical compositions comprising the polymers and at least one agent.

(10) The polymers are cross-linkable block polymers comprising monomer units which include boronic acid moieties, and monomer units which include polyol-containing moieties. The boronic acid and polyol-containing moieties enable the polymers to self-assemble because the boronic acids react with diols, with the loss of water, to yield cyclic boronic esters (boronates). The polymer monomer units comprise boronic acid which reversibly binds to another polymer monomer unit comprising diols (i.e., polyols; polyhydroxyls) to form a network of cyclic boronic esters (boronates) in aqueous media (or other solvents) under appropriate conditions. For example, a monomer unit comprising a sugar saccharide unit (such as a glucose moiety, which contains diols) serves as a way to cross-link to the boronic acid monomer unit. In certain embodiments, the resulting polymeric gel (e.g., hydrogels) can be prepared using other agents such that the other agents are encapsulated within the cross-linked polymer matrix. In certain embodiments, the polymeric gel is injectable and can be used to deliver an agent to the subject or target tissue. In certain embodiments, the agent is delivered when physiological conditions (e.g., pH, salt concentration, temperature) are appropriate for reversing the boronic ester bonds. In certain embodiments, the agent diffuses out of the polymeric gel or matrix.

(11) The polymers described herein are prepared using a free radical polymerization process, which results in polymers with randomly ordered monomeric units. The boronic acid monomers can reversibly bind to the diol groups of polyol monomers, such as those with 1,2- or 1,3-dihydroxy substituents, including but not limited to monomers functionalized with sugar moieties (such as saccharide moieties, e.g., fructose, galactose, glucose, mannose, sucrose, lactulose, lactose, maltose, trehalose, cellobiose, etc.). The saccharide can be in the open chain form or the close ring form. The resulting covalent bond between the boronic acid moieties and the diol moieties create a cross-linked polymeric gel matrix.

(12) Provided herein are methods of preparing the polymers by free radical polymerization. Various monomer units can be used to prepare the polymers. In certain embodiments, the method comprises polymerizing boronic-acid containing monomers and amine-containing monomers. In certain embodiments, the method comprises polymerizing boronic-acid containing monomers, amine-containing monomers, and one or more additional monomers via a free-radical polymerization reaction. In certain embodiments, the method comprises polymerizing boronic-acid containing monomers, amine-containing monomers, aliphatic monomers, and optionally the one or more additional monomers via a free-radical polymerization reaction. In certain embodiments, the method comprises polymerizing boronic-acid containing monomers, amine-containing monomers, aliphatic monomers via a free-radical polymerization reaction.

(13) In certain embodiments, the method comprises polymerizing boronic-acid containing monomers and polyol-containing monomers. In certain embodiments, the method comprises polymerizing boronic-acid containing monomers, polyol-containing monomers, and one or more additional monomers via a free-radical polymerization reaction. In certain embodiments, the method comprises polymerizing boronic-acid containing monomers, polyol-containing monomers, aliphatic monomers, and optionally the one or more additional monomers via a free-radical polymerization reaction. In certain embodiments, the method comprises polymerizing boronic-acid containing monomers, polyol-containing monomers, aliphatic monomers via a free-radical polymerization reaction.

(14) The polymers described herein are prepared using free radical polymerization involving a radical initiator. Radical initators are known in the art. There are radical initiators that are activated by heat (thermal initiator) or light (photoinitiator) to form free radicals that initiate the polymerization reaction.

(15) In certain embodiments, the radical initiator is a thermal initiator. Any thermal initiator may be used in the polymerization reaction. In certain embodiments, a combination of thermal initiators is used. In certain embodiments, the thermal initiator is designed to work at a temperature ranging from 30 C. to 200 C. In certain embodiments, the initiator is designed to work at a temperature ranging from 50 C. to 170 C. In other embodiments, the initiator is designed to work at a temperature ranging from 50 C. to 100 C. In certain embodiments, the initiator is designed to work at a temperature ranging from 100 C. to 170 C. In certain particular embodiments, the initiator is designed to work at approximately 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, or 170 C. The thermal initiators may be but are not limited to peroxides, peracids, peracetates, and persulfates. Exemplary thermal initiators include tert-amyl peroxybenzoate; 4,4-azobis (4-cyanovaleric acid); 1,1-azobis (cyclohexanecarbonitrile); 2,2-azobisisobutyronitrile (AIBN); benzoyl peroxide; 2,2-bis (tert-butylperoxy) butane; 1,1-bis(tert-butylperoxy)cyclohexane; 2,5-bis (tert-butylperoxy)-2,5-dimethylhexane; 2,5-bis(tert-butylperoxy)-2,5-dimethyl-3-hexyne; bis(1-(tert-butylperoxy)-1-methylethyl)benzene; 1,1-bis (tert-butylperoxy)-3,3,5-trimethylcyclohexane; tert-butyl hydroperoxide; tert-butyl peracetate; tert-butyl peroxide; tert-butyl peroxybenzoate; tert-butylperoxy isopropyl carbonate; cumene hydroperoxide; cyclohexanone peroxide; dicumyl peroxide; lauroyl peroxide; 2,4-pentanedione peroxide; peracetic acid; potassium persulfate; diisopropyl peroxide carbonate; t-butyl peroxy-2-ethylhexanoate, t-butylperneodecanoate, t-butylperbenzoate; t-butyl percrotonate, t-butyl perisobutyrate, di-t-butyl perphthalate and 2,2-azo-bis(2-methylbutanenitrile). In certain embodiments, the radical initiator is AIBN.

(16) In certain embodiments, the radical initiator is a photoinitiator. Any photoinitiator may be used in the polymerization reaction. In certain embodiments, a combination of photoinitiators is used. Photoinitiated polymerizations and photoinitiators are discussed in detail in Rabek, Mechanisms of Photophysical Processes and Photochemical Reactions in Polymers, New York: Wiley & Sons, 1987; Fouassier, Photoinitiation, Photopolymerization, and Photocuring: Fundamentals and Applications (Cincinnati, Ohio: Hanser Gardner, 1995); Fisher et al., Photoinitiated Polymerization of Biomaterials Annu. Rev. Mater. Res. (2001) 31: 171-81; each of which are incorporated herein by reference. The photoinitiator may be designed to produce free radicals at any wavelength of light. In certain embodiments, the photoinitiator is designed to work using UV light (200-400 nm). In certain embodiments, long UV rays are used. In other embodiments, short UV rays are used. In other embodiments, the photoinitiator is designed to work using visible light (400-800 nm). In certain embodiments, the photoinitiator is designed to work using blue light (420-500 nm). In yet other embodiments, the photinitiator is designed to work using IR light (800-2500 nm). Exemplary photoinitiators include acetophenone; anisoin; anthraquinone; anthraquinone-2-sulfonic acid, sodium salt monohydrate; (benzene) tricarbonylchromium; benzin; benzoin; benzoin ethyl ether; benzoin isobutyl ether; benzoin methyl ether; benzophenone; benzophenone/1-hydroxycyclohexyl phenyl ketone; 3,3,4,4-benzophenonetetracarboxylic dianhydride; A-benzoylbiphenyl; 2-benzyl-2-(dimethylamino)-4-morpholinobutyrophenone; 4,4-bis(diethylamino)benzophenone; 4,4-bis(dimethylamino)benzophenone; camphorquinone; 2-chlorothioxanthen-9-one; (cumene)cyclopentadienyliron(II) hexafluorophosphate; dibenzosuberenone; 2,2-diethoxyacetophenone; 4,4-dihydroxybenzophenone; 2,2-dimethoxy-2-phenylacetophenone; 4-(dimethylamino)benzophenone; 4,4-dimethylbenzil; 2,5-dimethylbenzophenone; 3,4-dimethylbenzophenone; diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide/2-hydroxy-2-methylpropiophenone; 4-ethoxyacetophenone; 2-ethylanthraquinone; ferrocene; 3-hydroxyacetophenone; 4-hydroxyacetophenone; 3-hydroxybenzophenone; 4-hydroxybenzophenone; 1-hydroxycyclohexyl phenyl ketone; 2-hydroxy-2-methylpropiophenone; 2-methylbenzophenone; 3-methylbenzophenone; methybenzoylformate; 2-methyl-4-(methylthio)-2-morpholinopropiophenone; phenanthrenequinone; 4-phenoxyacetophenone; thioxanthen-9-one; triarylsulfonium hexafluoroantimonate salts; triarylsulfonium hexafluorophosphate salts; hydrogen peroxide; benzoyl peroxide; benzoin; 2,2-dimethoxy-2-phenylacetophenone; dibenzoyl disulphides; diphenyldithiocarbonate; 2, 2-azobisisobutyronitrile (AIBN); camphorquinone (CQ); eosin; dimethylaminobenzoate (DMAB); dimethoxy-2-phenyl-acetophenone (DMPA); Quanta-cure ITX photosensitizer (Biddle Sawyer); Irgacure 907 (Ciba Geigy); Irgacure 651 (Ciba Geigy); Darocur 2959 (Ciba Geigy); ethyl-4-N,N-dimethylaminobenzoate (4EDMAB); 1-[-(4-benzoylphenylsulfanyl)phenyl]-2-methyl-2-(4-methylphenylsulfonyl) propan-1-one; 1-hydroxy-cyclohexyl-phenyl-ketone; 2,4,6-trimethylbenzoyldiphenylphosphine oxide; 2-ethylhexyl-4-dimethylaminobenzoate; 2-hydroxy-2-methyl-1-phenyl-1-propanone; 65% (oligo[2-hydroxy-2-methyl-1-[4-(1-methylvinyl)phenyl]propanone] and 35% propoxylated glyceryl triacrylate; benzil dimethyl ketal; benzophenone; blend of benzophenone and a-hydroxy-cyclohexyl-phenyl-ketone; blend of Esacure KIP 150 and Esacure TZT; blend of Esacure KIP 150 and Esacure TZT; blend of Esacure KIP 150 and TPGDA; blend of phosphine oxide, Esacure KIP 150 and Esacure TZT; difunctional a-hydroxy ketone; ethyl A-(dimethylamino) benzoate; isopropyl thioxanthone; liquid blend of 4-methylbenzophenone and benzophenone; oligo(2-hydroxy-2 methyl-1-4 (1-methylvinyl)phenyl propanone (emulsion); oligo(2-hydroxy-2-methyl-1-4 (1-methylvinyl)phenyl propanone and 2-hydroxy-2-methyl-1-phenyl-1-propanone (monomeric); oligo (2-hydroxy-2-methyl-1-4 (1-methylvinyl) phenyl propanone and 2-hydroxy-2-methyl-1-phenyl-1-propanone (polymeric); trimethylbenzophenone and methylbenzophenone; and water emulsion of 2,4,6-trimethylbenzoylphosphine oxide, alpha hydroxyketone, trimethylbenzophenone, and A-methyl benzophenone. In certain embodiments, the photoinitiator is dimethoxy-2-phenyl-acetophenone (DMPA).

(17) The free radical polymerization process is performed under conditions suitable to yield the desired properties of the resulting polymer. For example, the extent of polymerization may be controlled by the time of the reaction, the amount/concentration of initiator, the type of starting monomers used, the initiator, the frequency of the light used, additives, temperature of the reaction, solvent used, concentration of starting materials, oxygen inhibition, water inhibition, etc., as would be appreciated by those of skill in the art.

(18) The polymers described herein are capable of self-assembling into hydrogels in aqueous solution (e.g., water). In certain embodiments, about 2-10% w/w polymer in aqueous solution are self-assembled to form hydrogels. In certain embodiments, about 5% w/w polymer in aqueous solution are self-assembled to form hydrogels. In certain embodiments, about 10-20% w/w polymer in aqueous solution are self-assembled to form hydrogels. In certain embodiments, about 20-30% w/w polymer in aqueous solution are self-assembled to form hydrogels.

(19) The polymers described herein have similar rheological properties to one another. The frequency dependence of the storage and loss oscillatory shear moduli (G and G, respectively) is consistent with hydrogel-like behavior, as the G and G curves are linear and parallel with G is dominant across the whole range of frequencies studied (see the FIGURE).

(20) Boronic Acid Monomer

(21) The boronic acid-containing monomer can be any boronic acid monomer that is compatible with free radical polymerization. This monomer can typically bind to a polyol-containing monomer unit. The polymers herein are prepared using a free-radical polymerization process comprising a boronic acid-containing monomer of Formula (A):

(22) ##STR00018##
or a salt thereof, wherein:

(23) each instance of R.sup.AA is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2;

(24) each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring;

(25) k is 0, 1, 2, 3, or 4;

(26) L.sup.A is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LA, or C(O), wherein R.sup.LA is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; and

(27) each instance of R.sup.A is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl.

(28) As defined generally above, each instance of R.sup.AA is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2. In certain embodiments, R.sup.AA is halogen (e.g., Br, F, I, Cl). In certain embodiments, R.sup.AA is substituted or unsubstituted alkyl. In certain embodiments, R.sup.AA is unsubstituted alkyl. In certain embodiments, R.sup.AA is unsubstituted alkyl. In certain embodiments, R.sup.AA is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.AA is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.AA is methyl, ethyl, or propyl.

(29) As defined generally above, each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring. In certain embodiments, R.sup.a is independently hydrogen. In certain embodiments, R.sup.a is substituted or unsubstituted acyl. In certain embodiments, R.sup.a is substituted or unsubstituted alkyl. In certain embodiments, R.sup.a is substituted or unsubstituted carbocyclyl. In certain embodiments, R.sup.a is substituted or unsubstituted heterocyclyl. In certain embodiments, R.sup.a is substituted or unsubstituted aryl. In certain embodiments, R.sup.a is substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.a is a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom. In certain embodiments, two instances of R.sup.a are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring.

(30) As defined generally above, k is 0, 1, 2, 3, or 4. In certain embodiments, k is 0. In certain embodiments, k is 1, 2, 3, or 4. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4.

(31) As defined generally above, L.sup.A is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LA, or C(O), wherein R.sup.LA is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, L.sup.A is a unsubstituted C.sub.1-6 alkylene chain. In certain embodiments, L.sup.A is a unsubstituted C.sub.3-6 alkylene chain. In certain embodiments, L.sup.A is a unsubstituted C.sub.1-3 alkylene chain. In certain embodiments, one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LA, or C(O), wherein each instance of R.sup.LA is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, one or more chain atoms of the alkylene chain are independently replaced with NR.sup.LA or C(O). In certain embodiments, one chain atoms of the alkylene chain is replaced with NR.sup.LA and another chain atom of the alkylene chain is replaced with C(O). In certain embodiments, two chain atoms of the alkylene chain is replaced with C(O)NR.sup.LA. In certain embodiment, both chain atoms of a C.sub.2 alkylene chain is replaced with C(O)NR.sup.LA. In certain embodiment, two chain atoms of a C.sub.3-6 alkylene chain is replaced with C(O)NR.sup.LA. In certain embodiments, one or more chain atoms of the alkylene chain are independently replaced with O or C(O). In certain embodiments, one chain atoms of the alkylene chain is replaced with O and another chain atom of the alkylene chain is replaced with C(O). In certain embodiments, two chain atoms of the alkylene chain is replaced with C(O)O. In certain embodiment, both chain atoms of a C.sub.2 alkylene chain is replaced with C(O)O. In certain embodiment, two chain atoms of a C.sub.3-6 alkylene chain is replaced with C(O)O. In certain embodiments, one or more chain atoms of the alkylene chain are independently replaced with C(O). In certain embodiments, L.sup.A is C(O)N(R.sup.LA), C(O)O, or C(O)(CH.sub.2).sub.n, wherein n is 1, 2, 3, 4, or 5. In certain embodiments, L.sup.A is C(O)N(R.sup.LA). In certain embodiments, L.sup.A is C(O)O. In certain embodiments, L.sup.A is C(O)(CH.sub.2).sub.n, wherein n is 1, 2, 3, 4, or 5. For any of the foregoing embodiments wherein one or more chain atoms of the alkylene chain are independently replaced with NR.sup.LA, the following embodiments of R.sup.LA are applicable. In certain embodiments, R.sup.LA is hydrogen. In certain embodiments, R.sup.LA is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.LA is a nitrogen protecting group.

(32) As defined generally above, each instance of R.sup.A is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is hydrogen. In certain embodiments, all R.sup.A are hydrogen. In certain embodiments, three R.sup.A are hydrogen, and one R.sup.A is a substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.A is substituted or unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.A is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.A is methyl, ethyl, or propyl.

(33) In certain embodiments, the boronic acid-containing monomer is of the Formula (A-1), (A-2), or (A-3):

(34) ##STR00019##
or a salt thereof, wherein: n is 0, 1, 2, 3, 4, 5, or 6; and R.sup.LA is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group. In certain embodiments, n is 0. In certain embodiments, n is 1, 2, 3, 4, 5, or 6. In certain embodiments, R.sup.LA is hydrogen. In certain embodiments, R.sup.LA is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, n is 0; and R.sup.LA is hydrogen. In certain embodiments, the boronic acid-containing monomer is of the formula:

(35) ##STR00020##
In certain embodiments, the boronic acid-containing monomer is of the formula:

(36) ##STR00021##
In any of the foregoing embodiments for the boronic acid-containing monomer, the boronic-acid moiety can be in the meta, para, or ortho position on the phenyl ring. In certain embodiments, the boronic-acid moiety is in the meta position. In certain embodiments, the boronic-acid moiety is in the para position. In certain embodiments, the boronic-acid moiety is in the ortho position. In certain embodiments, the boronic acid-containing monomer is of the formula:

(37) ##STR00022##
In certain embodiments, the boronic acid-containing monomer is of the formula:

(38) ##STR00023##
Amine-Containing Monomer

(39) In certain embodiments, the polymers are prepared via free radical polymerization using boronic acid-containing monomers and amine-containing monomers, which can subsequently be functionalized with polyol-containing moieties. The amine-containing monomers comprise protected amines, which can be deprotected prior to being functionalized with polyol-containing moieties. In certain embodiments, one or more types of additional monomers are used in the polymerization reaction to provide the polymers described herein.

(40) The amine-containing monomer is of Formula (B):

(41) ##STR00024##
or a salt thereof, wherein

(42) each instance of R.sup.B is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl;

(43) R.sup.N is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl;

(44) R.sup.NPG is a nitrogen protecting group; and

(45) L.sup.B is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O), wherein R.sup.LB is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group.

(46) As defined generally above, each instance of R.sup.B is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B is hydrogen. In certain embodiments, R.sup.B are all hydrogen. In certain embodiments, three R.sup.B are hydrogen, and one R.sup.B is a substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, one to three R.sup.B groups is an substituted or unsubstituted C.sub.1-6 alkyl and the remaining R.sup.B groups are hydrogen. In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.B is substituted or unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.B is unsubstituted C.sub.1-3 alkyl. In certain embodiments, R.sup.B is methyl, ethyl, or propyl.

(47) As defined generally above, R.sup.N is hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N is hydrogen. In certain embodiments, R.sup.N is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.N is an unsubstituted C.sub.1-6 alkyl.

(48) General and specific embodiments for L.sup.A as recited for Formula (A) are also applicable to L.sup.B for Formula (B). General and specific embodiments for R.sup.LA as recited for Formula (A) are also applicable to R.sup.LB for Formula (B).

(49) In certain embodiments, the amine-containing monomer is of the formula:

(50) ##STR00025##
wherein L.sup.B1 is a substituted or unsubstituted, C.sub.1-4 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O). In certain embodiments, the amine-containing monomer is of the formula:

(51) ##STR00026##
wherein q is 1, 2, 3, 4, 5, or 6. In certain embodiments, the amine-containing monomer is of Formula (B-1):

(52) ##STR00027##
wherein q is 1, 2, 3, 4, 5, or 6 and R.sup.NPG is a nitrogen protecting group. In certain embodiments, the amine-containing monomer is of Formula (B-2):

(53) ##STR00028##
wherein q is 1, 2, 3, 4, 5, or 6 and R.sup.NPG is a nitrogen protecting group. In certain embodiments, q is 1, 2, or 3. In certain embodiments, q is 3. In certain embodiments, the amine-containing monomer is of the formula:

(54) ##STR00029##
In certain embodiments, the amine-containing monomer is of Formula (B-3):

(55) ##STR00030##
In certain embodiments, R.sup.NPG is a nitrogen protecting group that is deprotected under acidic conditions. In certain embodiments, R.sup.NPG is a nitrogen protecting group that is deprotected (e.g., at least 90% deprotected after contacting the nitrogen protecting group with an acidic condition for 24 hours) below pH 1. In certain embodiments, R.sup.NPG is a nitrogen protecting group that is deprotected below pH 2. In certain embodiments, R.sup.NPG is a nitrogen protecting group that is deprotected below pH 3. In certain embodiments, R.sup.NPG is a nitrogen protecting group that is deprotected below pH 4. In certain embodiments, R.sup.NPG is Boc.

(56) In certain embodiments, the amine-containing monomer is of Formula (B-3)

(57) ##STR00031##
In certain embodiments, R.sup.NPG is triphenylmethyl. In certain embodiments, R.sup.NPG is a nitrogen protecting group that is deprotected under basic conditions (e.g., above pH 7, above pH 9, above pH 11, or above pH 13). In certain embodiments, R.sup.NPG is trifluoroacetyl. In certain embodiments, R.sup.NPG is a nitrogen protecting group that is deprotected by a nucleophile, electrophile, reductant, or oxidant.

(58) In certain embodiments, the protected amines of the polymer are deprotected to provide a polymer with free amines. Methods of nitrogen deprotection are known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated herein by reference. For example, if the nitrogen protecting group is tert-butyloxycarbonyl (BOC), trifluoroacetic acid (TFA) can be used for BOC deprotection.

(59) In certain embodiments, polymers with free amines are reacted with a sugar. In certain embodiments, the sugar is in the cyclic form. In certain embodiments, the sugar is in the open chain form. In certain embodiments, polymers with free amines are reacted with an aldehyde or ketone of Formula (E):

(60) ##STR00032##
or a salt thereof, in the presence of a reductant, wherein:

(61) R.sup.E is hydrogen, substituted or unsubstituted alkyl;

(62) s is an integer between 1 and 10, inclusive; and

(63) X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, or C(O)N(R.sup.a).sub.2. In certain embodiments, the aldehyde or ketone is a sugar. In certain embodiments, the aldehyde or ketone is a saccharide, such as glucose, galactose, or mannose, in the open chain aldehyde form. In certain embodiments, the aldehyde or ketone is a five-membered ring saccharide. In certain embodiments, the aldehyde or ketone is a saccharide, such as fructose, in the open chain ketone form. Common reductants useful for reductive amination include, but are not limited to, sodium borohydride (NaBH.sub.4), sodium cyanoborohydride (NaBH.sub.3CN), and sodium triacetoxyborohydride (NaBH(OAc).sub.3). In certain embodiments, the reductant is NaBH(OAc).sub.3.

(64) As defined generally above, R.sup.E is hydrogen, substituted or unsubstituted alkyl. In certain embodiments, R.sup.E is hydrogen. In certain embodiments, R.sup.E is a substituted alkyl. In certain embodiments, R.sup.E is an alkyl substituted with hydroxyl. In certain embodiments, R.sup.E is CH.sub.2OH. In certain embodiments, R.sup.E is an unsubstituted alkyl.

(65) As defined generally above, s is an integer between 1 and 10, inclusive. In certain embodiments, s is an integer between 1 and 5, inclusive. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. In certain embodiments, s is 4. In certain embodiments, s is 5. In certain embodiments, s is 6. In certain embodiments, s is 7. In certain embodiments, s is 8. In certain embodiments, s is 9. In certain embodiments, s is 10. It is understood that the carbon connected to the hydroxyl group will be asymmetric. It is understood that the stereochemistry at each instance of asymmetric carbon on the alkylene chain can vary.

(66) As defined generally above, X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, or C(O)N(R.sup.a).sub.2. In certain embodiments, X is hydrogen. In certain embodiments, X is substituted or unsubstituted alkyl. In certain embodiments, X is unsubstituted alkyl. In certain embodiments, X is substituted alkyl. In certain embodiments, X is substituted or unsubstituted C.sub.1-3 alkyl. In certain embodiments, X is substituted C.sub.1-3 alkyl. In certain embodiments, X is methyl, ethyl, or propyl. In certain embodiments, X is methyl, ethyl, or propyl, wherein each can be substituted with a hydroxyl. In certain embodiments, X is methyl substituted with a hydroxyl (i.e., CH.sub.2OH). Each instance of R.sup.a is defined above for Formula (A). The specific embodiments for R.sup.a as recited for Formula (A) are also applicable to Formula (E).

(67) In certain embodiments, R.sup.E is hydrogen, s is 1, and X is methyl substituted with a hydroxyl (i.e., CH.sub.2OH). For example, the aldehyde or ketone of Formula (E) can be glyceraldehyde. In certain embodiments, R.sup.E is hydrogen, s is 4, and X is methyl substituted with a hydroxyl (i.e., CH.sub.2OH). For example, the aldehyde or ketone of Formula (E) can be glucose, mannose, or galactose. In certain embodiments, R.sup.E is hydrogen, m is 3, and X is methyl substituted with a hydroxyl (i.e., CH.sub.2OH). For the example, the aldehyde or ketone of Formula (E) can be ribose. In certain embodiments, when s is between 2 and 10, a hydroxyl moiety on the alkylene chain can be replaced with H. In certain embodiments, when s is 3, one hydroxyl moiety is replaced with H. For example, the aldehyde or ketone of Formula (E) can be deoxyribose.

(68) In certain embodiments, R.sup.E is CH.sub.2OH, s is 2, and X is CH.sub.2OH. For example, the aldehyde or ketone of Formula (E) can be ribulose. In certain embodiments, R.sup.E is CH.sub.2OH, s is 3, and X is CH.sub.2OH. For example, the aldehyde or ketone of Formula (E) can be fructose.

(69) In certain embodiments, an aldehyde described can be oxidized to form an the corresponding uronic acid, wherein the terminal carbon's hydroxyl group has been oxidized to the a carboxylic acid. For example, a sugar aldehyde such as glucose can form glucoronic acid after oxidation. In certain embodiments, X is COOH.

(70) In certain embodiments, polymers with free amines are reacted with a cylic sugar of Formula (E-1):

(71) ##STR00033##
or a salt thereof. The general and specific embodiments for R.sup.E are as defined for Formula (E). The general and specific embodiments for R are as defined for Formula (C). The general and specific embodiments for n are as recited for Formula (C-2). The general and specific embodiments for X as recited for Formula (E) are also applicable to X.sub.1 for Formula (E-1). In certain embodiments, the cyclic sugar of Formula (E-1) is glucose, galactose, or mannose. In certain embodiments, the cyclic sugar of Formula (E-1) is fructose or another 5-membered ring sugar. In certain embodiments, the cyclic sugar can be a disaccharide. In certain embodiments, the disaccharide is sucrose, sucrose, lactulose, lactose, maltose, trehalose, or cellobiose.
Polyol-Containing Monomer

(72) In certain embodiments, the polymers are prepared via free radical polymerization using boronic acid-containing monomers and polyol-containing monomers.

(73) In certain embodiments, the second monomer is a polyol of the following formula:

(74) ##STR00034##
In certain embodiments, the sugar can be in the cyclic form (i.e., closed ring form). In certain embodiments, the sugar can be in the linear form (i.e., open chain form). In certain embodiments, the sugar (either cyclic or linear form) is derived from a saccharide such as, but not limited to, glucose, mannose, galactose, fructose, ribulose, ribose, or deoxyribose.

(75) In certain embodiments, the second monomer is a polyol of Formula (C):

(76) ##STR00035##
or a salt thereof, wherein:

(77) R is H, substituted or unsubstituted, C.sub.1-6 alkyl, or an oxygen protecting group;

(78) X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)R.sup.a, C(O)OR.sup.a, or C(O)N(R.sup.a).sub.2;

(79) m is an integer between 2 and 10, inclusive;

(80) L.sup.C is a substituted or unsubstituted, C.sub.1-15 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LC, or C(O), wherein each instance of R.sup.LC is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; and

(81) each instance of R.sup.C is independently hydrogen, or substituted or unsubstituted, C.sub.1-6 alkyl.

(82) In certain embodiments, R is H. In certain embodiments, R is a oxygen protecting group. General and specific embodiments for R.sup.A as recited for Formula (A) are also applicable to R.sup.C for Formula (C). General and specific embodiments for L.sup.A as recited for Formula (A) are also applicable to L.sup.C for Formula (C). General and specific embodiments for R.sup.LA as recited for Formula (A) are also applicable to R.sup.LC for Formula (C). General and specific embodiments for X as recited for Formula (E) are also applicable to X for Formula (C). The general and specific embodiments for R.sup.a as recited for Formula (A) are also applicable to R.sup.a for Formula (C).

(83) General and specific embodiments for s as recited for Formula (E) are also applicable to m for Formula (C).

(84) In certain embodiments, the polyol-containing monomer is of the Formula (C-1):

(85) ##STR00036##
or a salt thereof, wherein R is H or a oxygen protecting group and p is 1, 2, 3, 4, 5, or 6. In certain embodiments, R is H. In certain embodiments, R is a oxygen protecting group. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, p is 6. m is defined above for Formula (C). The specific embodiments for m as recited for Formula (C) are also applicable to Formula (C-1). R.sup.C is defined above for Formula (C). The specific embodiments for R.sup.C as recited for Formula (C) are also applicable to Formula (C-1). R.sup.LB is defined above for Formula (B). The specific embodiments for R.sup.LB as recited for Formula (B) are also applicable to Formula (C-1). X is defined above for Formula (C). The specific embodiments for X as recited for Formula (C) are also applicable to Formula (C-1).

(86) In certain embodiments, X is CH.sub.2OH. In certain embodiments, m is 1; and X is CH.sub.2OH. In certain embodiments, m is 2; and X is CH.sub.2OH. In certain embodiments, m is 3; and X is CH.sub.2OH. In certain embodiments, m is 4; and X is CH.sub.2OH. In certain embodiments, m is 5; and X is CH.sub.2OH. In certain embodiments, when m is between 2 and 10, the hydroxyl moiety on the alkylene chain of Formula (C-1) can be replaced with H. In certain embodiments, when m is 3, one hydroxyl moiety is replaced with H. In certain embodiments, R.sup.C are all H.

(87) In certain embodiments, R.sup.C are all H; and X is (CH.sub.2)OH. In certain embodiments, the polyol-containing monomer is of the formula:

(88) ##STR00037##
or a salt thereof, wherein R.sup.LB is as recited for Formula (B), R are as defined for Formula (C), m is as recited for Formula (C), and p is as recited for Formula (C-1). In certain embodiments, p is 3; and m is 4. In certain embodiments, p is 3; and m is 3. In certain embodiments, p is 3; and m is 2. In certain embodiments, p is 3; and m is 1. In certain embodiments, p is 2; and m is 4. In certain embodiments, p is 2; and m is 3. In certain embodiments, p is 2; and m is 2. In certain embodiments, p is 2; and m is 1.

(89) In certain embodiments, the polyol-containing monomer is of the formula:

(90) ##STR00038##
wherein L.sup.C1 is a substituted or unsubstituted, C.sub.1-8 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O). In certain embodiments, the polyol-containing monomer is of the formula:

(91) ##STR00039##
wherein p is 1, 2, 3, 4, 5, or 6. In certain embodiments, the polyol-containing monomer is of the formula

(92) ##STR00040##
In certain embodiments, the polyol-containing monomer is of the formula:

(93) ##STR00041##
wherein p is 1, 2, 3, 4, 5, or 6.

(94) In certain embodiments, the second monomer is a polyol of Formula (C-2):

(95) ##STR00042##
or a salt thereof, wherein R.sup.c, L.sup.C, and R are as defined for Formula (C), and n is an integer between 1 and 3, inclusive. General and specific embodiments for X as recited for Formula (E) are also applicable to X.sub.1 for Formula (C-2). In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 1, and X.sub.1 is CH.sub.2OH. In certain embodiments, n is 2, and X.sub.1 is H.
Aliphatic Monomer

(96) The polymer can optionally be prepared using an aliphatic monomer in any of the described polymerization reactions. The aliphatic monomer is used to tune the hydrogel properties such as hydrophobicity and pKa. In certain embodiment, the polymer is prepared using an aliphatic monomer in any of the described polymerization reactions. In certain embodiment, the polymer is prepared using boronic acid-containing monomers, amine-containing monomers, and an aliphatic monomer in any of the described polymerization reactions. The aliphatic monomer is of Formula (D):

(97) ##STR00043##
or a salt thereof, wherein:

(98) each instance of R.sup.D is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl;

(99) L.sup.D is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LD, or C(O), wherein R.sup.LD is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; and

(100) R.sup.D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.D2, or NR.sup.D2.sub.2, wherein R.sup.D2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, optionally wherein one or more chain atoms of an alkyl chain are independently replaced with alkenyl, O, NR.sup.LD, or C(O).

(101) General and specific embodiments for R.sup.A as recited for Formula (A) are also applicable to R.sup.D for Formula (D). General and specific embodiments for L.sup.A as recited for Formula (A) are also applicable to L.sup.D for Formula (D). General and specific embodiments for R.sup.LA as recited for Formula (A) are also applicable to R.sup.LD for Formula (D).

(102) As defined generally above, R.sup.D is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.D is H. In certain embodiments, R.sup.D are all H. In certain embodiments, R.sup.D is unsubstituted C.sub.1-6 alkyl. In certain embodiments, three instances of R.sup.D is H and one instead of R.sup.D is unsubstituted C.sub.1-6 alkyl. In certain embodiments, three instances of R.sup.D is H and one instead of R.sup.D is unsubstituted methyl.

(103) As defined generally above, R.sup.D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.D2, or NR.sup.D2.sub.2, wherein R.sup.D2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, optionally wherein one or more chain atoms of an alkyl chain are independently replaced with alkenyl, O, NR.sup.LD, or C(O). In certain embodiments, R.sup.D1 is H. In certain embodiments, R.sup.D1 is substituted or unsubstituted alkyl. In certain embodiments, R.sup.D1 is unsubstituted alkyl. In certain embodiments, R.sup.D1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, R.sup.D1 is substituted alkyl. In certain embodiments, R.sup.D1 is substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.D1 is methyl, ethyl, or propyl. In certain embodiments, R.sup.D1 is isopropyl. In certain embodiments, R.sup.D1 is OR.sup.D2, wherein R.sup.D2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl. In certain embodiments, R.sup.D1 is NR.sup.D2.sub.2, wherein R.sup.D2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl. In certain embodiments, R.sup.D1 is an alkyl substituted with COOH. In certain embodiments, R.sup.D1 is an alkyl chain wherein one or more chain atoms are replaced with alkenyl, O, NR.sup.LD, or C(O). When a monomer or polymer described herein includes two or more instances of R.sup.D2, any two instances of R.sup.D2 may be the same or different from each other.

(104) In certain embodiments, the aliphatic monomer is of the Formula (D-1):

(105) ##STR00044##
or a salt thereof. The specific embodiments for R.sup.D as recited for Formula (D) are also applicable to Formula (D-1). The specific embodiments for R.sup.D1 as recited for Formula (D) are also applicable to Formula (D-1). In certain embodiments, R.sup.D is H. In certain embodiments, R.sup.D is methyl. In certain embodiment, R.sup.D of any of the below embodiments of Formula (D-1) is a C.sub.1-6 alkyl. In certain embodiment, R.sup.D of any of the below embodiments of Formula (D-1) is a methyl.

(106) In certain embodiments, the aliphatic monomer is of the formula:

(107) ##STR00045##
In certain embodiments, the aliphatic monomer is of the formula:

(108) ##STR00046##
wherein R.sup.D1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, the aliphatic monomer is of the formula:

(109) ##STR00047##
wherein R.sup.D1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, the aliphatic monomer is

(110) ##STR00048##
In certain embodiments, the aliphatic monomer is

(111) ##STR00049##
In certain embodiments, the aliphatic monomer is.

(112) ##STR00050##
In certain embodiments, the aliphatic monomer is

(113) ##STR00051##
In certain embodiments, the third monomer is

(114) ##STR00052##
In certain embodiments, R.sup.D1 of any of the above embodiments of Formula (D-1) is an alkyl chain substituted with COOH. In certain embodiments, the aliphatic monomer is

(115) ##STR00053##
In certain embodiments, R.sup.D1 of any of the above embodiments of Formula (D-1) is an alkyl chain wherein one or more chain atoms are replaced with alkenyl, O, NR.sup.LD, or C(O). In certain embodiments, the aliphatic monomer is.

(116) ##STR00054##
Ratio of Monomer Units

(117) The ratios of the various monomers are chosen to optimize polymeric gel network properties including mechanical properties, permeability, swelling index, and/or gel strength using principles known in the art. Since the polymers described herein are prepared using a free radical polymerization process, the monomer units will be randomly arranged within the polymer.

(118) In certain embodiments, the ratio (molar ratio) of the boronic acid-containing monomer to either the amine-containing monomer or the polyol-containing monomer in the polymerization reaction is about 1:1 to about 1:10. In certain embodiments, the ratio (molar ratio) of the boronic acid-containing monomer to either the amine-containing monomer or the polyol-containing monomer in the polymerization reaction is about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

(119) In certain embodiments, the ratio (molar ratio) of the boronic acid-containing monomer to either the amine-containing monomer or the polyol-containing monomer in the polymerization reaction is about 10:1 to about 1:1. In certain embodiments, the ratio (molar ratio) of the boronic acid-containing monomer to either the amine-containing monomer or the polyol-containing monomer in the polymerization reaction is about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1.

(120) In certain embodiments, polymerization reaction comprises a ratio (molar ratio) of aliphatic monomers to boronic acid-containing monomers to either the amine-containing monomers or polyol-containing monomers that is about 18:1:1, 8:1:1, 70:15:15, 3:1:1, 2:1:1, 40:30:30, 30:35:35, 1:2:2, 10:45:45, 0:1:9, or 0:1:1.

(121) In certain embodiments, the ratio of boronic acid-containing units to either the polyol-containing units or the amine-containing units is about 1 unit of boronic acid-containing unit to about 1 unit of either the polyol-containing units or the amine-containing units. In certain embodiments, the ratio of boronic acid-containing units to either the polyol-containing units or the amine-containing units is about 1 unit of boronic acid-containing unit to at least about 2 units of either the polyol-containing units or the amine-containing units. In certain embodiments, the ratio of boronic acid-containing units to either the polyol-containing units or the amine-containing units is at least about 2 units of boronic acid-containing unit to about 1 unit of either the polyol-containing units or the amine-containing units.

(122) In certain embodiments, the polymer comprises about 0-95% of the aliphatic monomer, about 5%-60% of the boronic acid-containing monomer, and about 5%-95% of the amine-containing monomer. In certain embodiments, the polymer comprises about 0-95% of the aliphatic monomer, about 5%-60% of the boronic acid-containing monomer, and about 5%-95% of the polyol-containing monomer.

(123) In certain embodiments, the polymer comprises both amine-containing units and polyol-containing units. In certain embodiments, the polymer comprises boronic acid-containing monomer, amine-containing units and polyol-containing units. In certain embodiments, the polymer comprises about 5-90% amine-containing units and 5-90% polyol-containing units. In certain embodiments, the polymer comprises about 0-95% of the aliphatic monomer, about 5%-60% of the boronic acid-containing monomer, about 5%-95% of the amine-containing monomer, and about 5%-95% of the polyol-containing monomer.

(124) In certain embodiments, the polymer comprises about 1%-99% of the boronic acid-containing monomer, and about 1%-99% of the polyol-containing monomer. In certain embodiments, the polymer comprises about 5%-95% of the boronic acid-containing monomer, and about 5%-95% of the polyol-containing monomer. In certain embodiments, the polymer comprises about 1%-10% of the boronic acid-containing monomer, and about 90-99% of the polyol-containing monomer. In certain embodiments, the polymer comprises about 10%-30% of the boronic acid-containing monomer, and about 70%-90% of the polyol-containing monomer. In certain embodiments, the polymer comprises about 30%-60% of the boronic acid-containing monomer, and about 40-70% of the polyol-containing monomer. In certain embodiments, the polymer comprises about 60%-80% of the boronic acid-containing monomer, and about 20-40% of the polyol-containing monomer. In certain embodiments, the polymer comprises about 80%-99% of the boronic acid-containing monomer, and about 1%-20% of the polyol-containing monomer.

(125) In certain embodiments, the polymer comprises about 1%-99% of the boronic acid-containing monomer, and about 1%-99% of the amine-containing monomer. In certain embodiments, the polymer comprises about 5%-95% of the boronic acid-containing monomer, and about 5%-95% of the amine-containing monomer. In certain embodiments, the polymer comprises about 1%-10% of the boronic acid-containing monomer, and about 90-99% of the amine-containing monomer. In certain embodiments, the polymer comprises about 10%-30% of the boronic acid-containing monomer, and about 70%-90% of the amine-containing monomer. In certain embodiments, the polymer comprises about 30%-60% of the boronic acid-containing monomer, and about 40-70% of the amine-containing monomer. In certain embodiments, the polymer comprises about 60%-80% of the boronic acid-containing monomer, and about 20-40% of the amine-containing monomer. In certain embodiments, the polymer comprises about 80%-99% of the boronic acid-containing monomer, and about 1%-20% of the amine-containing monomer.

(126) Polymers

(127) In another aspect, the present disclosure provides polymers. In certain embodiments, a provided polymer comprises a plurality of side chains with boronic acid-containing moieties, polyol-containing moieties or amine-containing moieties, aliphatic moieties, and optionally one or more additional types of monomer moieties. In certain embodiments, a provided polymer is of Formula (I):

(128) ##STR00055##
comprising a plurality of side chains with boronic acid-containing moieties, polyol-containing moieties or amine-containing moieties, aliphatic moieties, and optionally one or more additional types of monomer moieties, wherein:

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

(130) t is 2 to 2000; and

(131) each instance of R is independently a side chain is selected from:

(132) boronic acid-containing moieties of Formula (a):

(133) ##STR00056##

(134) wherein:

(135) each instance of R.sup.AA is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2;

(136) each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring;

(137) k is 0, 1, 2, 3, or 4;

(138) L.sup.A is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LA, or C(O), wherein each instance of R.sup.LA is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; and

(139) polyol-containing moieties of Formula (c):

(140) ##STR00057##

(141) wherein:

(142) X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)R.sup.a, C(O)OR.sup.a, or C(O)N(R.sup.a).sub.2;

(143) m is an integer between 1 and 10, inclusive;

(144) L.sup.C is a substituted or unsubstituted, C.sub.1-10 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O), wherein each instance of R.sup.LB is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group;

(145) amine-containing moieties of Formula (b):

(146) ##STR00058##

(147) wherein:

(148) R.sup.LB is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;

(149) R.sup.LC is a nitrogen protecting group; and

(150) L.sup.B is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB-, or C(O), wherein each instance of R.sup.LB is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; and

(151) optionally, aliphatic moieties of Formula (d):

(152) ##STR00059##

(153) wherein:

(154) each instance of R.sup.D is independently hydrogen or substituted or unsubstituted C.sub.1-6 alkyl;

(155) L.sup.D is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LD, or C(O), wherein R.sup.LD is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; and

(156) R.sup.D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.D2, or NR.sup.D22, wherein R.sup.D2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, optionally wherein one or more chain atoms of an alkyl chain are independently replaced with alkenyl, O, NR.sup.LD, or C(O).

(157) In certain embodiments, a provided polymer is of Formula (I), or a salt thereof, wherein:

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

(159) t is 2 to 2000; and

(160) each instance of R is independently a side chain selected from:

(161) boronic acid-containing moieties of Formula (a):

(162) ##STR00060##

(163) wherein:

(164) each instance of R.sup.AA is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.a, N(R.sup.a).sub.2, SR.sup.a, CN, SCN, C(NR.sup.a)R.sup.a, C(NR.sup.a)OR.sup.a, C(NR.sup.a)N(R.sup.a).sub.2, C(O)R.sup.a, C(O)OR.sup.a, C(O)N(R.sup.a).sub.2, NO.sub.2, NR.sup.aC(O)R.sup.a, NR.sup.aC(O)OR.sup.a, NR.sup.aC(O)N(R.sup.a).sub.2, OC(O)R.sup.a, OC(O)OR.sup.a, or OC(O)N(R.sup.a).sub.2;

(165) each instance of R.sup.a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.a are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring;

(166) k is 0, 1, 2, 3, or 4;

(167) L.sup.A is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LA, or C(O), wherein each instance of R.sup.LA is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group; and

(168) polyol-containing moieties of Formula (c):

(169) ##STR00061##

(170) wherein:

(171) X is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)R.sup.a, C(O)OR.sup.a, or C(O)N(R.sup.a).sub.2;

(172) m is an integer between 1 and 10, inclusive;

(173) L.sup.C is a substituted or unsubstituted, C.sub.1-10 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB-, or C(O), wherein each instance of R.sup.LB is independently hydrogen, substituted or unsubstituted, C.sub.1-6 alkyl, or a nitrogen protecting group;

(174) amine-containing moieties of Formula (b):

(175) ##STR00062##

(176) wherein:

(177) R.sup.N is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl;

(178) R.sup.NPG is a nitrogen protecting group; and

(179) L.sup.B is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O), wherein each instance of R.sup.LB is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; and

(180) optionally, aliphatic moieties of Formula (d):

(181) ##STR00063##

(182) wherein:

(183) L.sup.D is a substituted or unsubstituted, C.sub.1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LD, or C(O), wherein R.sup.LD is independently hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; and

(184) R.sup.D1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR.sup.D2, or NR.sup.D2.sub.2, wherein R.sup.D2 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkenyl, optionally wherein one or more chain atoms of an alkyl chain are independently replaced with alkenyl, O, NR.sup.LD, or C(O).

(185) In some embodiments, two instances of X.sup.A are the same. In other embodiments, two instances of X.sup.A are different from each other. In certain embodiments, at least one instance of X.sup.A is hydrogen. In certain embodiments, each instance of X.sup.A is hydrogen. In certain embodiments, at least one instance of X.sup.A is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of X.sup.A is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of X.sup.A is OR.sup.XA or N(R.sup.XA).sub.2. In certain embodiments, at least one instance of X.sup.A is C(O)N(R.sup.XA).sub.2.

(186) In certain embodiments, at least one instance of R.sup.A is hydrogen. In certain embodiments, each instance of R.sup.XA is hydrogen. In certain embodiments, at least one instance of R.sup.XA is substituted or unsubstituted acyl. In certain embodiments, at least one instance of R.sup.XA is substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.XA is substituted or unsubstituted C.sub.1-6 alkyl (e.g., Me). In certain embodiments, at least one instance of R.sup.XA is substituted or unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.XA is substituted or unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.XA is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.XA is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.XA is a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom. In certain embodiments, two instances of R.sup.XA are joined to form a substituted or unsubstituted, heterocyclic ring, or substituted or unsubstituted, heteroaryl ring.

(187) In certain embodiments, a boronic acid-containing moiety of Formula (a) is of the formula:

(188) ##STR00064##
wherein n is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, a boronic acid-containing moiety of Formula (a) is of the formula:

(189) ##STR00065##
wherein n is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, a boronic acid-containing moiety of Formula (a) is of the formula:

(190) ##STR00066##
In certain embodiments, a boronic acid-containing moiety of Formula (a) is of the formula:

(191) ##STR00067##
In certain embodiments, a boronic acid-containing moiety of Formula (a) is of the formula:

(192) ##STR00068##
In certain embodiments, a boronic acid-containing moiety of Formula (a) is of the formula:

(193) ##STR00069##

(194) In certain embodiments, a polyol-containing moiety of Formula (c) is of the formula:

(195) ##STR00070##
wherein L.sup.C1 is a substituted or unsubstituted, C.sub.1-8 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O). In certain embodiments, a polyol-containing moiety of Formula (c) is of the formula:

(196) ##STR00071##
wherein p is 1, 2, 3, 4, 5, or 6. In certain embodiments, a polyol-containing moiety of Formula (c) is of the formula:

(197) ##STR00072##
In certain embodiments, a polyol-containing moiety of Formula (c) is of the formula:

(198) ##STR00073##
wherein p is 1, 2, 3, 4, 5, or 6.

(199) In certain embodiments, an amine-containing moieties of Formula (b) is of the formula:

(200) ##STR00074##
wherein L.sup.B1 is a substituted or unsubstituted, C.sub.1-4 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with O, NR.sup.LB, or C(O). In certain embodiments, an amine-containing moieties of Formula (b) is of the formula:

(201) ##STR00075##
wherein q is 1, 2, 3, or 4. In certain embodiments, an amine-containing moieties of Formula (b) is of the formula:

(202) ##STR00076##
In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(203) ##STR00077##
In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(204) ##STR00078##
wherein R.sup.D1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(205) ##STR00079##
wherein R.sup.D1 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(206) ##STR00080##
In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(207) ##STR00081##
In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(208) ##STR00082##
wherein R.sup.D1 is substituted C.sub.1-6 alkyl (e.g., C.sub.1-6 alkyl substituted with C(O)OH). In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(209) ##STR00083##
In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(210) ##STR00084##
wherein R.sup.D1 is an alkyl chain, wherein one or more chain atoms are replaced with alkenyl, O, NR.sup.LD, or C(O). In certain embodiments, an aliphatic moieties of Formula (d) is of the formula:

(211) ##STR00085##

(212) In certain embodiments, a polymer of Formula (I) comprises a plurality of side chains selected from:

(213) ##STR00086##

(214) In certain embodiments, a polymer of Formula (I) comprises a plurality of side chains selected from:

(215) ##STR00087##

(216) In certain embodiments, a polymer of Formula (I) comprises a plurality of side chains selected from:

(217) ##STR00088##

(218) In certain embodiments, a polymer of Formula (I) comprises a plurality of side chains selected from:

(219) ##STR00089##

(220) In certain embodiments, a polymer of Formula (I) comprises a plurality of side chains selected from:

(221) ##STR00090##

(222) In certain embodiments, a polymer of Formula (I) comprises a plurality of side chains selected from:

(223) ##STR00091##

(224) In a provided polymer, the ratio of the boronic acid-containing moiety, polyol-containing moiety or amine-containing moiety, aliphatic moiety, and the additional types of monomer moieties to each other is as described herein (e.g., as described for the monomers described herein).

(225) In certain embodiments, t is between 10 and 2000, inclusive. In certain embodiments, t is between 100 and 2000, inclusive. In certain embodiments, t is between 300 and 2000, inclusive. In certain embodiments, t is between 1000 and 2000, inclusive. In certain embodiments, t is between 2 and 10, inclusive. In certain embodiments, t is between 10 and 30, inclusive. In certain embodiments, t is between 10 and 100, inclusive. In certain embodiments, t is between 10 and 300, inclusive. In certain embodiments, t is between 10 and 1000, inclusive.

(226) In certain embodiments, the molecular weight of a provided polymer is between 1,000 and 3,000, inclusive. In certain embodiments, the molecular weight of a provided polymer is between 1,000 and 10,000, inclusive. In certain embodiments, the molecular weight of a provided polymer is between 1,000 and 30,000, inclusive. In certain embodiments, the molecular weight of a provided polymer is between 1,000 and 100,000, inclusive. In certain embodiments, the molecular weight of a provided polymer is between 1,000 and 1000,000, inclusive. In certain embodiments, the molecular weight of a provided polymer is between 3,000 and 100,000, inclusive. In certain embodiments, the molecular weight of a provided polymer is between 10,000 and 100,000, inclusive. In certain embodiments, the molecular weight of a provided polymer is between 30,000 and 100,000, inclusive. In certain embodiments, the molecular weight of a provided polymer is weight-average molecular weight (e.g., weight-average molecular weight as measured by static light scattering).

(227) Uses and Compositions

(228) The polymers described herein and polymeric gels thereof can be used for the delivery of agents (e.g., as drug or cell delivery devices) or as part of a material (e.g., coating, device). The use of the polymer and polymeric gels thereof will depend on the physical and chemical properities of the polymer. Chemical properties include pKa, degradation time, ionizability, hydrophobicity, hydrophilicity, reactivity, etc. The use of the material will also depend on the mechanical properites of the polymer. These properites include hardness, elasticity, strength, stiffness, flexibility, etc.

(229) The polymer and polymeric gels thereof may be used for fabricating medical devices.

(230) The polymer and polymeric gels thereof may be useful in drug or cell delivery. For example, the polymer and polymeric gels thereof may be used in forming particles, such as nanoparticles, microparticles, and macroparticles, capsules, coatings, or larger depots of an agent, including therapeutic agent, diagnostic agent, or prophylatic agent. In certain embodiments, the agents to be delivered is combined with the polymers described herein or with the polymeric gels thereof, and a therapeutically effective amount of the combination is administered to a subject (e.g., mammals such as human). Agents is more fully described below.

(231) Agent

(232) Agents that are delivered by the compositions described herein (e.g., pharmaceutical compositions) may be pharmaceutical (e.g., therapeutic or prophylactic), diagnostic, imaging, 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.

(233) By adding agents to the polymers described herein before the gelling process, the agents can be distributed throughout the resulting polymer scaffold. Depending on the specific applications, various combinations of polymer monomers provided herein, as well as other monomers known to those of ordinary skill in the art, can be used to provide the polymeric gels with desired physical characteristics, such as mechanical strength, degradability after injection or implantation, and/or desired biological properties, such as biocompatibility, the ability to provide a biologically relevant microenvironment, or ability to target or recognize specific tissue sites. The polymer chain length, composition, initiation concentration, and other factors can be varied to allow control of the density and degree of polymer scaffold crosslinking.

(234) 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 antifungal agent), anesthetic, steroidal agent, anti-proliferative agent, anti-inflammatory agent, anti-angiogenesis agent, anti-neoplastic agent, anti-cancer agent, anti-diabetic agent, antigen, vaccine, antibody, decongestant, antihypertensive, sedative, birth control agent, progestational agent, anti-cholinergic, analgesic, immunosuppressant, anti-depressant, anti-psychotic, -adrenergic blocking agent, diuretic, cardiovascular active agent, vasoactive agent, non-steroidal, nutritional agent, anti-allergic agent, or pain-relieving agent. Vaccines may comprise isolated proteins or peptides, inactivated organisms and viruses, dead organisms and viruses, genetically altered organisms or viruses, and cell extracts. Therapeutic and prophylactic agents may be combined with interleukins, interferon, cytokines, and adjuvants such as cholera toxin, alum, and Freund's adjuvant, etc.

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

(236) 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.

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

(238) 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.

(239) 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.

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

(241) 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.

(242) 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.

(243) 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.

(244) 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.

(245) In certain embodiments, the agent is one or more types of cells. Cell-laden hydrogels are useful for tissue-engineering applications. For example, fibroblasts, osteoblasts, vascular smooth muscle cells, and chondrocytes can be encapsulated in the polymer scaffolds.

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

(247) 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.

(248) 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.

(249) Targeting Agents

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

(251) Particles

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

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

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

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

(256) 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.

(257) 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.

(258) 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).

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

(260) Micelles, Liposomes, and Lipoplexes

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

(262) 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, Preparation of Vesicles (Liposomes) In Encylopedia of Nanoscience and Nanotechnology; Nalwa, H. S. Ed. American Scientific Publishers: Los Angeles, 2004; Vol. 9, pp. 43-79; Szoka et al., Comparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes) Ann. Rev. Biophys. Bioeng. 9:467-508, 1980; each of which is incorporated herein by reference. The preparation of lipsomes may involve preparing a polymer described herein for hydration, hydrating the polymer with agitation, and sizing the vesicles to achieve a homogenous distribution of liposomes. A polymer described herein may be first dissolved in a solvent in a container to result in a homogeneous mixture. The solvent is then removed to form a film. This film is thoroughly dried to remove residual amount of the solvent, e.g., by placing the container in vacuo for a period of time. Hydration of the film may be accomplished by adding an aqueous medium and agitating the resulting mixture. Disruption of LMV suspensions using sonic energy typically produces small unilamellar vesicles (SUV) with diameters in the range of 15-50 nm. Lipid extrusion is a technique in which a lipid suspension is forced through a polycarbonate filter with a defined pore size to yield particles having a diameter near the pore size of the filter used. Extrusion through filters with 100 nm pores typically yields large, unilamellar vesicles (LUV) with a mean diameter of 120-140 nm. In certain embodiments, the amount of a polymer described herein in the liposome is between about 30 mol % and about 80 mol %, between about 40 mol % and about 70 mol %, or between about 60 mol % and about 70 mol %, inclusive. In certain embodiments, the polymer further complexes an agent, such as a polynucleotide.

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

(264) Ratio of Agent to Polymer

(265) The present disclosure contemplates that the polymers described herein are useful in the delivery of an agent described herein to a subject, tissue, or cell.

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

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

(268) In certain embodiments, the compositions comprises about 10 wt % to about 90% wt % of the polymer. In certain embodiments, the compositions comprises about 20 wt % to about 90% wt % of the polymer. In certain embodiments, the compositions comprises about 30 wt % to about 90% wt % of the polymer. In certain embodiments, the compositions comprises about 40 wt % to about 90% wt % of the polymer. In certain embodiments, the compositions comprises about 50 wt % to about 90% wt % of the polymer. In certain embodiments, the compositions comprises about 60 wt % to about 90% wt % of the polymer. In certain embodiments, the compositions comprises about 70 wt % to about 90% wt % of the polymer.

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

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

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

(272) Compositions

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

(274) In certain embodiments, the composition further comprises a solvent. In certain embodiments, the solvent is water. In certain embodiments, the composition comprises a gel. In certain embodiments, the composition comprises a hydrogel.

(275) In another aspect, provided herein are compositions comprising the polymers or polymeric gels thereof and at least one or more agents. 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. 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).

(276) 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.

(277) 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.

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

(279) 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.

(280) 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.

(281) 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.

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

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

(284) 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.

(285) 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 about 0.1% and about 50% (w/w) active ingredient.

(286) 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.

(287) 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.

(288) 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.

(289) 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.

(290) 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.

(291) 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.

(292) 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.

(293) 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.

(294) 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.

(295) 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.

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

(297) 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.

(298) 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.

(299) 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.

(300) 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.

(301) 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.

(302) 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.

(303) 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.

(304) 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.

(305) 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.

(306) 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.

(307) 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.

(308) 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.

(309) 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.

(310) 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.

(311) 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.

(312) Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. 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. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration.

(313) 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.

(314) 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.

(315) 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).

(316) 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.

(317) 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.

(318) 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.

(319) 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.

(320) Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical 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 pharmaceutical 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.

(321) Polymers and polymeric gels provided 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 invention 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.

(322) 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).

(323) The exact amount of a polymer or polymeric gel 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 compound(s), 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).

(324) 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.

(325) 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.

(326) 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.

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

(328) 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.

(329) Methods of Treatment and Uses

(330) 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.

(331) 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.

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

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

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

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

(336) 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).

(337) 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.

(338) 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.

(339) 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.

(340) 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.

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

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

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

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

(345) Kits

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

(347) 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.

(348) In certain embodiments, the described kits further include instructions for administering a polymer (or polymeric gel thereof) 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.

EXAMPLES

(349) In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

Example 1. Preparation of a Library of Polymer Based Injectable Hydrogels

(350) The library of block polymers were designed and synthesized using radical polymerization reactions. Monomers B and C were polymerized with AIBN as an initiator in order to afford polymer BC, which was subsequently deprotected by trifluoroacetic acid (TFA) to provide polymer BCNH.sub.2. Reductive amination of polymer BCNH.sub.2 and glucose in methanol at room temperature gives the final product. Eleven different polymers (BG 1-11) were obtained by varying the ratio of monomer B and C in the initial polymerization. Structures of all polymers (BC and BCNH.sub.2) were confirmed with .sup.1H NMR. These polymers were able to self-assemble to injectable hydrogels. The general synthesis of the polymer is shown below:

(351) ##STR00092##

(352) General Procedures of Polymer Synthesis.

(353) A heating block which can hold 20 ml vials was preheated to 65 C. 20 ml of glass vials with septa were used in multi reactions set up. 3-(Acrylamino)phenylboronic acid (B; PBA) and tert-butyl (3-acrylamidopropyl)carbamate (C; RNHBoc) in a desired ratio were dissolved in MeOH (3.5 ml) at rt with stirring. Nitrogen was purged in solution for 30 minutes. 12.5% of 2,2-Azobis(2-methylpropionitrile) (recrystallized before using) was added. The solution was continuously degassed for an additional 30 minutes, heated at 65 C. with stirring for one day, then cooled to rt. It was dropwise added to a 200 ml Et.sub.2O. The precipitate was filtered by suction, washed with Et.sub.2O (350 ml), dried to get a white solid. Yield: 100% of B in synthesis, yields 86%; 90:10% of B/C in synthesis, yields 82%; 80:20% of B/C in synthesis, yields 92%; 70:30% of B/C in synthesis, yields 91%; 60:40% of B/C in synthesis, yields 90%; 50:50% of B/C in synthesis, yields 84%; 40:60% of B/C in synthesis, yields 80%; 30:70% of B/C in synthesis, yields 87%; 20:80% of B/C in synthesis, 68%; yields 10:90% of B/C in synthesis, yields 62%; 100% of C in synthesis, yields 78%.

(354) General Procedures of De-Protection.

(355) To a polymer (200 mg) were added dichloromethane (6 ml) followed by TFA (3 ml). The suspension was stirred at room temperature (rt) for one day. The solvents were evaporated on rotavap. Methanol was added to dissolve oily residue and evaporated subsequently. This procedure was repeated for three times to get rid of excess TFA as much as possible to leave a white solid, which was dried further under high vacuum pump overnight.

(356) General Procedures of Reductive Amination

(357) A mixture of de-protected polymer, glucose and sodium triacetoxyborohydride in DMF (3 ml) and THF (6 ml) was stirred at rt for one day. The amount of glucose (1 equiv.) and sodium triacetoxyborohydride (1.2 equiv.) depended on amount of C in polymer synthesis. Majority solvents were evaporated. The residue was dissolved in ultra-pure water (20 ml), dialyzed (MWCO 1,000) and lyophilized to have a white solid.

(358) Polymer structure characterization by .sup.1HNMR:

(359) ww-5-86, 100:0 of PBA:RNHBoc:

(360) .sup.1HNMR (500 MHz, CD3OD): 8.06-6.82 (m, 5H), 2.69-1.34 (m, 3H);

(361) ww-5-87, 90:10 of PBA:RNHBoc:

(362) .sup.1HNMR (500 MHz, CD3OD): 8.02-6.86 (m, 5H), 3.23-1.27 (m, 6H);

(363) ww-5-88, 80:20 of PBA:RNHBoc:

(364) .sup.1HNMR (500 MHz, CD3OD): 7.99-6.94 (m, 5H), 3.23-1.27 (m, 8H);

(365) ww-5-89, 70:30 of PBA:RNHBoc:

(366) .sup.1HNMR (500 MHz, CD3OD): 8.05-6.91 (m, 5H), 3.27-1.26 (m, 15H);

(367) ww-5-90, 60:40 of PBA:RNHBoc:

(368) .sup.1HNMR (500 MHz, CD3OD): 8.03-6.94 (m, 5H), 3.27-1.25 (m, 16H);

(369) ww-5-98, 50:50 of PBA:RNHBoc:

(370) .sup.1HNMR (500 MHz, CD3OD): 8.03-6.93 (m, 5H), 3.27-1.20 (m, 19H);

(371) ww-5-91, 40:60 of PBA:RNHBoc:

(372) .sup.1HNMR (500 MHz, CD3OD): 8.12-7.00 (m, 5H), 3.28-1.26 (m, 25H);

(373) ww-5-92, 30:70 of PBA:RNHBoc:

(374) .sup.1HNMR (500 MHz, CD3OD): 8.03-7.04 (m, 5H), 3.25-1.23 (m, 36H);

(375) ww-5-93, 20:80 of PBA:RNHBoc:

(376) .sup.1HNMR (500 MHz, CD3OD): 8.06-7.14 (m, 5H), 3.28-1.24 (m, 49H);

(377) ww-5-94, 10:90 of PBA:RNHBoc:

(378) .sup.1HNMR (500 MHz, CD3OD): 8.03-7.11 (m, 5H), 3.29-1.33 (m, 95H);

(379) ww-5-95, 0:100 of PBA:RNHBoc:

(380) .sup.1HNMR (500 MHz, CD3OD): 3.28-3.14 (m, 2H), 3.14-3.01 (m, 2H), 2.40-1.52 (m, 5H), 1.45 (s, 9H);

(381) ww-6-29, 90:10 of PBA:RNH.sub.2.TFA:

(382) .sup.1HNMR (500 MHz, D.sub.2O): 7.98-6.52 (m, 5H), 3.54-0.74 (m, 4H);

(383) ww-6-30, 80:20 of PBA:RNH.sub.2.TFA:

(384) .sup.1HNMR (500 MHz, D.sub.2O): 7.83-6.50 (m, 5H), 3.50-0.75 (m, 7H);

(385) ww-6-8, 70:30 of PBA:RNH.sub.2.TFA: N/A

(386) ww-6-66, 60:40 of PBA:RNH.sub.2.TFA:

(387) .sup.1HNMR (500 MHz, CD.sub.3OD): 7.72-6.81 (m, 5H), 3.42-1.12 (m, 9H);

(388) ww-5-84, 50:50 of PBA:RNH.sub.2.TFA:

(389) .sup.1HNMR (500 MHz, CD.sub.3OD): 7.87-6.94 (m, 5H), 3.28-1.37 (m, 14H);

(390) ww-6-18, 40:60 of PBA:RNH.sub.2.TFA:

(391) .sup.1HNMR (500 MHz, D.sub.2O): 7.77-6.78 (m, 5H), 3.41-1.24 (m, 19H);

(392) ww-6-19, 30:70 of PBA:RNH.sub.2.TFA:

(393) .sup.1HNMR (500 MHz, D.sub.2O): 7.85-6.91 (m, 5H), 3.43-1.24 (m, 29H);

(394) ww-6-23, 20:80 of PBA:RNH.sub.2.TFA:

(395) .sup.1HNMR (500 MHz, D.sub.2O): 8.01-6.90 (m, 5H), 3.25-1.28 (m, 40H);

(396) ww-6-24, 10:90 of PBA:RNH.sub.2.TFA:

(397) .sup.1HNMR (500 MHz, D.sub.2O): 7.93-7.11 (m, 5H), 3.38-1.24 (m, 82H);

(398) ww-6-35, 0:100 of PBA:RNH.sub.2.TFA:

(399) .sup.1HNMR (500 MHz, D.sub.2O): 3.37-3.08 (m, 2H), 3.03-2.92 (m, 2H), 2.26-1.30 (m, 5H).

(400) As shown in the scheme below, polymers were also prepared with an optional monomer (A).

(401) ##STR00093##
The ratio of monomers A, B, and C used to prepare polymer ABC are provided below in Table 1.

(402) TABLE-US-00001 TABLE 1 The ratio of A, B and C used (mmoles) for synthesis of polymer ABC Point Polymer ABC .sup.1HNMR ID Point A % B % Point C % (mg) (CD3OD) ww-4-63 100 0 0 72 ww-4-59 90 5 5 181 ww-4-74 80 10 10 378 ww-4-75 70 15 15 408 ww-4-77 60 20 20 490 ww-4-78 50 25 25 520 ww-4-85 40 30 30 370 ww-4-86 30 35 35 376 ww-4-87 20 40 40 434 ww-4-88 10 45 45 495 ww-4-69 0 10 90 352 ww-4-94 0 50 50 461
Deprotection of Polymer ABC is Shown Below:

(403) ##STR00094##

(404) TABLE-US-00002 TABLE 2 List of polymer ABC-NH.sub.2 Polymer ABC used .sup.1HNMR Ratio of A:B:C (mg) Polymer ABC-NH.sub.2 (CD.sub.3OD) 100:0:0 ww-4-63 90:5:5 ww-4-59 (37 mg) ww-4-60 80:10:10 ww-4-74 (184 mg) ww-4-79B 70:15:15 ww-4-75 (200 mg) ww-4-80B 60:20:20 ww-4-77 (245 mg) ww-4-83 50:25:25 ww-4-78 (260 mg) ww-4-84 40:30:30 ww-4-85 (185 mg) ww-4-91 30:35:35 ww-4-86 (188 mg) ww-4-92 20:40:40 ww-4-87 (217 mg) ww-4-93 10:45:45 ww-4-88 (247 mg) ww-4-95 0:10:90 ww-4-69 (150 mg) ww-4-71A 0:50:50 ww-4-94 (230 mg) ww-4-96
The synthesis of polymer ABC-glucose (ABG) is provided below:

(405) ##STR00095##

(406) TABLE-US-00003 TABLE 3 List of Polymer ABG .sup.1HNMR Ratio of A:B:C Polymer ABC-NH.sub.2 Polymer ABG (mg) (D2O) 100:0:0 90:5:5 Different approach ww-4-58 (125 mg) ww-4-60 ww-4-61 (38.7 mg) 80:10:10 ww-4-79B ww-4-81 (159 mg) 70:15:15 ww-4-80B ww-4-82 (164 mg) 60:20:20 ww-4-83 ww-4-89 (203 mg) 50:25:25 ww-4-84 ww-4-90 (203 mg) 40:30:30 ww-4-91 ww-4-97 (151 mg) 30:35:35 ww-4-92 ww-4-98 (160 mg) 20:40:40 ww-4-93 ww-4-99 (152 mg) 10:45:45 ww-4-95 ww-4-100 (196 mg) 0:10:90 ww-4-71A ww-4-73 (483 mg) 0:50:50 ww-4-96 ww-5-1 (163 mg)

EQUIVALENTS AND SCOPE

(407) 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.

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

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

(410) Those killed 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.