Delivery of poly(ethylene glycol)-modified molecules from degradable hydrogels
View Patent ↗A degradable PEG hydrogel is described that, upon hydrolysis, releases conjugates of substantially non-peptidic polymers and biologically active molecules. For example, PEG and protein conjugates can be released in vivo from the hydrogels for therapeutic application.
1. A degradable crosslinked polymer structure, comprising a poly(ethylene glycol) molecule covalently attached to a biologically active molecule and having at least one hydrolytically unstable linkage in its backbone, and a branched, substantially non-peptidic polymer crosslinked to the poly(ethylene glycol) molecule, wherein the hydrolytically unstable linkage in the backbone of the poly(ethylene glycol) molecule is capable of degrading in aqueous solution to release a conjugate of the biologically active molecule and poly(ethylene glycol).
2. The polymer structure of claim 1 , wherein the branched, substantially non-peptidic polymer is a polymeric amine having a polymer backbone selected from the group consisting of poly(alkylene oxides), poly(oxyethylated polyols), poly(olefinic alcohols), poly(oxazoline), poly(vinylpyrrolidone), poly(acryloylmorpholine), and copolymers or terpolymers thereof.
3. The polymer structure of claim 1 , wherein the branched, substantially non-peptidic polymer is selected from the group consisting of poly(alkylene oxides), poly(oxyethylated polyols), poly(olefinic alcohols), poly(oxazoline), poly(vinylpyrrolidone), poly(acryloylmorpholine), and copolymers or terpolymers thereof.
4. The polymer structure of claim 1 , wherein the branched, substantially non-peptidic polymer does not have hydrolytically unstable linkages in its backbone.
5. The polymer structure of claim 1 , wherein the branched, substantially non-peptidic polymer is poly(ethylene glycol).
6. The polymer structure of claim 1 , wherein the at least one hydrolytically unstable linkage is selected from the group consisting of carboxylate ester, phosphate ester, hydrozone, orthoester, anhydride, imine, acetal, ketal, oligonucleotide, and peptide.
7. The polymer structure of claim 1 , wherein the hydrolytically unstable linkage is an ester linkage —O—(CHR′) r —CO 2 —, wherein r is 1–10, and R′ is hydrogen or alkyl.
8. The polymer structure of claim 1 , wherein the biologically active molecule is selected from the group consisting of enzymes, polypeptides, drugs, nucleosides, and phospholipids.
9. The polymer structure of claim 1 , wherein the biologically active molecule comprises at least one amine group.
10. The polymer structure of claim 1 , wherein the covalent linkage between the biologically active molecule and the poly(ethylene glycol) molecule having at least one hydrolytically unstable linkage in its backbone is a hydrolytically stable linkage.
11. The polymer structure of claim 10 , wherein the hydrolytically stable linkage is selected from the group consisting of amide, urethane, amine, ether, thioether, and urea.
12. The polymer structure of claim 1 , wherein the poly(ethylene glycol) molecule has at least two hydrolytically unstable linkages in its backbone.
13. The polymer structure of claim 1 , wherein the branched, substantially non-peptidic polymer has the structure R(CH 2 —O-poly-NH 2 ) p prior to crosslinking, wherein R is a central branching group, p is 3 to 10, and poly is a polymer selected from the group consisting of poly(alkylene oxides), poly(oxyethylated polyols), poly(olefinic alcohols), poly(oxazoline), poly(vinylpyrrolidone), poly(acryloylmorpholine), and copolymers or terpolymers thereof.
14. The polymer structure of claim 13 , wherein poly is poly(ethylene glycol).
15. The polymer structure of claim 13 , wherein R is selected from the group consisting of glycerol, glycerol oligomers, pentaerythritol, sorbitol, trimethyolpropane, and di(trimethylolpropane).
16. The polymer structure of claim 1 , wherein the poly(ethylene glycol) molecule has the formula X-PEG-W-PEG-T-D prior to crosslinking, wherein X is a terminal reactive group, W is a hydrolytically unstable linkage, T is a hydrolytically stable linkage, and D is the biologically active molecule.
17. The polymer structure of claim 16 , wherein X is selected from the group consisting of succinimidyl ester, sulfosuccinimidyl, benzotriazole, and p-nitrophenyl.
18. The polymer structure of claim 16 , wherein X is —O—(CH 2 ) n —CO 2 —NHS or —O—CO 2 NHS, wherein n is 1–10.
19. The polymer structure of claim 16 , wherein W is selected from the group consisting of carboxylate ester, phosphate ester, hydrozone, orthoester, anhydride, imine, acetal, ketal, oligonucleotide, and peptide.
20. The polymer structure of claim 16 , wherein W is —O—(CHR′) r —CO 2 —, wherein r is 1–10, and R′ is hydrogen or alkyl.
21. A degradable crosslinked polymer structure, comprising a first poly(ethylene glycol) molecule covalently attached to a biologically active molecule and having at least one hydrolytically unstable linkage in its backbone, and a second branched poly(ethylene glycol) crosslinked to the first poly(ethylene glycol) molecule, wherein the hydrolytically unstable linkage in the backbone of the first poly(ethylene glycol) molecule is capable of degrading in aqueous solution to release a conjugate of the biologically active molecule and poly(ethylene glycol), and wherein the second branched poly(ethylene glycol) does not have hydrolytically unstable linkages in its backbone.
22. The polymer structure of claim 21 , wherein the hydrolytically unstable linkage is selected from the group consisting of carboxylate ester, phosphate ester, hydrozone, orthoester, anhydride, imine, acetal, ketal, oligonucleotide, and peptide.
23. The polymer structure of claim 21 , wherein the hydrolytically unstable linkage is an ester linkage.
24. The polymer structure of claim 21 , wherein the branched poly(ethylene glycol) has the structure R(CH 2 —O-poly-NH 2 ) p prior to crosslinking, wherein R is a central branching group, p is 3 to 10, and poly is poly(ethylene glycol).
25. The polymer structure of claim 24 , wherein R is selected from the group consisting of glycerol, glycerol oligomers, pentaerythritol, sorbitol, trimethyolpropane, and di(trimethylolpropane).
26. A degradable crosslinked polymer structure, comprising a first poly(ethylene glycol) molecule covalently attached to a biologically active molecule through a hydrolytically stable linkage and having at least one hydrolytically unstable ester linkage in its backbone, and a second branched poly(ethylene glycol) crosslinked to the first poly(ethylene glycol) molecule, wherein the hydrolytically unstable ester linkage in the backbone of the first poly(ethylene glycol) molecule is capable of degrading in aqueous solution to release a conjugate of the biologically active molecule and poly(ethylene glycol), and wherein the second branched poly(ethylene glycol) does not have hydrolytically unstable linkages in its backbone.
27. The polymer structure of claim 26 , wherein the hydrolytically stable linkage is selected from the group consisting of amide, urethane, amine, ether, thioether, and urea.