Polymers, hydrogels, and uses thereof
Described herein are polymers, polymeric gels, or a composition thereof, for drug delivery. The polymers, which include boronic-acid containing moieties (e.g., and polyol-containing moieties (e.g., 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.
1. A polymer of Formula (I):
or a salt thereof, wherein:
X 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 XA , —N(R XA ) 2 , —C(═NR XA )R XA , —C(═NR XA )OR XA , —C(═NR XA )N(R XA ) 2 , —C(═O)R XA , —C(═O)OR XA , or —C(═O)N(R XA ) 2 , wherein each instance of R 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 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):
wherein:
each instance of R 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 a , —N(R a ) 2 , —SR a , —CN, —SCN, —C(═NR a )R a , —C(═NR a )OR a , —C(═NR a )N(R a ) 2 , —C(═O)R a , —C(═O)OR a , —C(═O)N(R a ) 2 , —NO 2 , —NR a C(═O)R a , —NR a C(═O)OR a , —NR a C(═O)N(R a ) 2 , —OC(═O)R a , —OC(═O)OR a , or —OC(═O)N(R a ) 2 ;
each instance of R 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 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 A is a substituted or unsubstituted, C 1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with —O—, —NR LA —, or —C(═O)—, wherein each instance of R LA is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, or a nitrogen protecting group; and
polyol-containing moieties of Formula (c):
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 a , —C(═O)OR a , or —C(═O)N(R a ) 2 ;
m is an integer between 1 and 10, inclusive;
L C is a substituted or unsubstituted, C 1-10 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with —O—, —NR LB —, or —C(═O)—, wherein each instance of R LB is independently hydrogen, substituted or unsubstituted, C 1-6 alkyl, or a nitrogen protecting group; and
amine-containing moieties of Formula (b):
wherein:
R N is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
R NPG is a nitrogen protecting group; and
L B is a substituted or unsubstituted, C 1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with —O—, —NR LB —, or —C(═O)—, wherein each instance of R LB is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group; and
aliphatic moieties of Formula (d):
wherein:
L D is a substituted or unsubstituted, C 1-6 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with —O—, —NR LD —, or —C(═O)—, wherein R LD is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group; and
R 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 D2 , or —NR D2 2 , wherein R 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 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 A are the same.
17. The polymer of claim 1 , wherein the two instances of X A are different.
18. The polymer of claim 1 , wherein at least one instance of X A is —OR XA or —N(R XA ) 2 .
19. The polymer of claim 1 , wherein at least one instance of X A is —C(═O)N(R XA ) 2 .
20. The polymer of claim 1 , wherein at least one instance of X A is hydrogen.
21. The polymer of claim 1 , wherein the boronic acid-containing moieties of Formula (a) are independently of the formula:
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:
wherein L B1 is a substituted or unsubstituted, C 1-4 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with —O—, —NR LB —, or —C(═O)—.
23. The polymer of claim 1 , wherein the polyol-containing moietis of Formula (c) are independently of the formula:
wherein L C1 is a substituted or unsubstituted, C 1-8 alkylene chain, optionally wherein one or more chain atoms of the alkylene chain are independently replaced with —O—, —NR LB —, or —C(═O)—.
24. The polymer of claim 1 , wherein the aliphatic moieties of Formula (d) are independently of the formula:
wherein R D1 is substituted or unsubstituted alkyl.
25. The polymer of claim 1 comprising a plurality of side chains selected from:
26. The polymer of claim 1 , comprising a plurality of side chains selected from:
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.