Biocompatible macromers

• US 20020028189A1
• Filed: 04/30/2001
• Published: 03/07/2002
• Est. Priority Date: 04/14/2000
• Status: Active Grant

• Current Assignee: Rice University
• Original Assignee: Rice University
• Inventors: Mikos, Antonios G., Jo, Seongbong
• Granted Patent: US 6,884,778 B2
• Time in Patent Office: Days
• US Class Current: 424/78.3
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: C08G 63/676 in which at least one of the two components contains aliphatic unsaturation
• CPC Class Codes: C08G 63/918 Polycarboxylic acids and polyhydroxy compounds in which at least one of the two components contains aliphatic unsaturation
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 65/3322 acyclic
• CPC Class Codes: C08G 81/025 containing polyether sequences
• CPC Class Codes: C08L 67/00 Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain of polyester-amides C08L77/12; of polyester-imides C08L79/08; Compositions of derivatives of such polymers

Abstract

A new oligomer based on alternating fumaric acid and poly(ethylene glycol) (PEG) units is provided. The oligo(PEG fumarate) (OPF) may be functionalized by modification with a biocompatible organic group. Further, the OPF may be cross-linked using radical polymerization in the presence of either a chemical or photo initiator. A cross-linked OPF gel has a swelling behavior that is tunable dependent on the molecular weight of PEG. A cross-linkable PEG macromer, as exemplified by oligo(PEG fumarate), has unsaturated double bonds, for example in the fumaryl groups, along its macromolecular chain that allows for the preparation of hydrogels with tailored structure and properties.

Claims

1. A macromer comprising an oligomer consisting essentially of a plurality of repeating units each consisting essentially of a cross-linkable moiety bound to a polymer, wherein each of said cross-linkable moiety and said polymer are biocompatible.

3. The macromer according to claim 1 wherein said polymer is a polyether.

4. The macromer according to claim 3 wherein said polyether is hydrophilic.

5. The macromer according to claim 4 wherein said polyether is poly(ethylene glycol).

6. The macromer according to claim 1 wherein said cross-linkable moiety comprises an unsaturated carbon bond between the ends of the cross-linkable moiety, wherein said ends have the same chemical composition.

7. The macromer according to claim 6 wherein said cross-linkable moiety is a fumaryl group.

8. The macromer according to claim 1 modified with a therapeutic agent.

9. The macromer according to claim 8 wherein said therapeutic agent comprising a biocompatible organic group selected from the group consisting of peptides, proteins, protein fragments, proteoglycans, glycoproteins, carbohydrates.

11. The macromer according to claim 9 modified with a biocompatible organic group selected from the group consisting of peptides, proteins, protein fragments, proteoglycans, glycoproteins, and carbohydrates.

12. The macromer according to claim 11 wherein the peptide is selected from the group consisting of RGD, YIGSR, REDV, IKVAV, and KRSR peptides.

13. The macromer according to claim 11 wherein the protein is selected from the group consisting of members of the transforming growth factor beta superfamily, bone morphogeneic proteins, basic fibroblast growth factor, platelet derived growth factor, insulin like growth factor, and extracellular matrix molecules including osteopontin, osteonectin, osteocalcin, and bone sialoprotein.

14. The macromer according to claim 11 wherein the protein fragments comprise fragments of the proteins selected from the group consisting of members of the transforming growth factor beta superfamily, bone morphogeneic proteins, basic fibroblast growth factor, platelet derived growth factor, insulin like growth factor, and extracellular matrix molecules including osteopontin, osteonectin, osteocalcin, and bone sialoprotein, comprising 3-30 amino acids.

15. The macromer according to claim 11 wherein the carbohydrate is selected from the group consisting of starch, cellulose, and chitin.

17. The macromer according to claim 16 modified with a biocompatible organic group selected from the group consisting of peptides, proteins, protein fragments, proteoglycans, glycoproteins, and carbohydrates.

18. The polymeric network according to claim 16 comprising oligo(poly(ethylene glycol)) cross-linked with oligo(poly(ethylene glycol) fumarate).

19. The polymeric network according to claim 16 comprising oligo(poly(ethylene glycol)) cross-linked with at least one linker molecule.

20. The polymeric network according to claim 19 wherein said linker molecule comprises a polymer comprising at least one unsaturated carbon-carbon bond.

21. The polymeric network according to claim 20 wherein said linker molecule comprises a diacrylated polymer.

22. The polymeric network according to claim 21 wherein said diacrylated polymer is selected from the group consisting of poly(propylene fumarate) and poly(ethylene glycol).

23. The polymeric network according to claim 16 wherein said polymeric network is water-swellable.

25. The method according to claim 24 wherein the polymeric network is water-swellable.

26. The method according to claim 25 wherein the wet to dry swelling ratio is tunable by varying the ratio of PEG to the fumaryl compound.

27. The method according to claim 25 wherein the wet to dry swelling ratio is tunable by varying the PEG molecular weight.

28. The method according to claim 24 further comprising cross-linking the fumaryl groups.

30. The method according to claim 29 wherein step (b) comprises dissolving dried OPF and a corresponding amount of 4-nitrophenylchloroformate in triethyl amine.

31. The method according to claim 29 wherein step (a) comprises forming the OPF by the reaction of fumaryl chloride with poly(propylene glycol).

32. The method according to claim 29 wherein the therapeutic agent comprises a biocompatible organic group is selected from the group consisting of peptides, proteins, protein fragments, proteoglycans, glycoproteins, and carbohydrates.

33. The method according to claim 25 further comprising:

(d) cross-linking the OPF with an unsaturated linker molecule.

34. The method according to claim 29 wherein the unsaturated linker comprises a polymer selected from the group consisting of PPF and PEG.

2. The macromer according to claim 2 wherein each of said cross-linkable moiety and said polymer are non-toxic.

10. A macromer comprising oligo(poly(ethylene glycol) fumarate).

16. A polymeric network comprising oligo(poly(ethylene glycol) fumarate).

24. A method of making a polymeric network comprising reacting PEG with a fumaryl compound in the presence of an organic base to form an oligo(PEG fumarate).

29. A method of making an OPF coupled to a therapeutic agent, comprising:

(a) providing an OPF;

(b) activating the OPF;

(c) coupling the therapeutic agent to the activated OPF; and