Functionalized polyester graft copolymers

• US 5,654,381 A
• Filed: 06/16/1995
• Issued: 08/05/1997
• Est. Priority Date: 06/16/1995
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Langer, Robert S., Hrkach, Jeffrey S., Lotan, Noah
• Primary Examiner(s): Acquah, Samuel A.
• Application Number:
  US08/491,490
• Time in Patent Office: 781 Days
• Field of Search: 528/361, 528/363, 525/425, 525/437, 525/450, 435/180, 424/418
• US Class Current: 525/450
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: C08G 63/6852 derived from hydroxy carboxylic acids
• CPC Class Codes: C08G 63/912 derived from hydroxycarboxylic acids
• CPC Class Codes: C08G 69/44 Polyester-amides

Abstract

Synthetic, functionalized, graft copolymers of polyesters and amino acids are provided. The copolymers are formed in one embodiment by providing a linear polyester-poly(amino acid) copolymer, and reacting the amino acid groups in the linear polymer with an amino acid derivative in a polymerization reaction to form a comb-like, graft copolymer including a polyester-amino acid backbone and polyamino acid side chains extending from the amino acid groups in the backbone. The poly(amino acid) includes functional groups which permit the covalent or ionic attachment of a biological molecule to the graft copolymer. The functionalized graft copolymers can be used in a wide range of biomedical applications including tissue engineering and drug delivery.

Claims

1. A biocompatible, graft copolymer formed by:

reacting a linear α

-hydroxy-acid polyester copolymer having at least one amino acid group incorporated therein and monomeric amino acid derivatives, to form a graft copolymer comprising a polyester copolymer and at least one poly(amino acid) side chain extending from an amino acid group in the polyester copolymer;

wherein the poly(amino acid) side chain includes at least one amino acid which comprises an ionically or covalently modifiable functional group.

2. The graft copolymer of claim 1 wherein the polyester copolymer comprises an α

-hydroxy acid selected from the group consisting of lactic acid, glycolic acid, hydroxybutyric acid and valeric acid, and mixtures thereof.

3. The graft copolymer of claim 1 wherein the linear α

-hydroxy-acid polyester copolymer comprises a poly(lactic acid) polymer having at least one lysine group incorporated therein; and

wherein the poly(amino acid) extends from at least one lysine group in the polyester copolymer.

4. The graft copolymer of claim 3 wherein the poly(amino acid) is a polymer of an amino acid selected from the group consisting of aspartic acid, lysine and alanine, and mixtures thereof.

5. The graft copolymer of claim 3 selected from the group consisting of a poly(L-lactic acid-co-L-lysine), a poly(L-lactic acid-co-β

-benzyl-L-aspartate), and a poly(L-lactic acid-co-D,L-alanine) graft copolymer.

6. The graft copolymer of claim 3 wherein the poly(amino acid) side chain includes between about 10 and 100 amino acids.

7. The graft copolymer of claim 3 having an amino acid content of between about 7 and 72%.

8. The graft copolymer of claim 1 wherein the functional group is covalently or ionically attached to a biological molecule.

9. The graft copolymer of claim 8 wherein the biological molecule is selected from the group consisting of a cell adhesion molecule, a growth factor, a drug, an antibody, a peptide and a protein.

10. The graft copolymer of claim 8 wherein the biological molecule includes a functional group selected from the group consisting of a hydrophilic group, a hydrophobic group, an acidic group, a basic group and an ionic group.

11. The graft copolymer of claim 8 wherein the modifiable functional group is selected from the group consisting of amino, carboxylic acid, sulfide, guanidino, imidazole and hydroxyl groups.

12. The graft copolymer of claim 8 wherein the modifiable functional group is a protonated amine ionically attached to the biological molecule;

and

wherein the biological molecule is selected from the group consisting of a polynucleotide and a polysaccharide.

29. The graft copolymer of claim 8 wherein the modifiable functional group is a protonated amine ionically attached to the biological molecule;

and

wherein the biological molecule is heparin.

30. The graft copolymer of claim 8 wherein the biological molecule alters a chemical or physical property of the graft copolymer.

31. The graft copolymer of claim 1 wherein the graft copolymer is biodegradable.

13. A method of forming a biocompatible graft copolymer, the method comprising:

reacting a linear α

-hydroxy-acid polyester copolymer, having at least one amino acid incorporated therein, in a polymerization reaction with monomeric amino acid derivatives thereby to form a graft copolymer comprising the polyester copolymer with a poly(amino acid) side chain extending from an amino acid group in the polyester copolymer;

wherein the poly(amino acid) side chain includes at least one amino acid which comprises an ionically or covalently modifiable functional group.

14. The matrix of claim 13 wherein at least a portion of the functional groups are covalently or ionically attached to an agent which promotes the stability of the drug.

15. The method of claim 13

wherein the method further includes covalently or ionically attaching a biological molecule to the functional group.

17. The method of claim 13 wherein the poly(amino acid) side chain includes between about 10 and 100 amino acids.

18. The method of claim 13 wherein the graft copolymer has an amino acid content of between about 7 and 72%.

19. The method of claim 13 wherein the polyester copolymer comprises an α

-hydroxy acid selected from the group consisting of lactic acid, glycolic acid, hydroxybutyric acid and valeric acid, and mixtures thereof.

20. The method of claim 14 wherein the polyester copolymer comprises a poly(lactic acid) polymer having at least one lysine group incorporated therein;

and

wherein the amino acid derivative is lysine N-carboxyanhydride which is reacted with the polyester copolymer to produce a poly(lysine) side chain extending from at least one lysine group in the polyester copolymer.

21. The method of claim 14 wherein the amino acid is selected from the group consisting of aspartic acid, lysine, alanine, and mixtures thereof.

22. The method of claim 13 wherein the graft copolymer is selected from the group consisting of a poly(L-lactic acid-co-L-lysine), a poly(L-lactic acid-co-β

-benzyl-L-aspartate), and a poly(L-lactic acid-co-D,L-alanine) graft copolymer.

23. The method of claim 15 wherein the biological molecule is selected from the group consisting of a peptide and a protein.

24. The method of claim 15 wherein the biological molecule includes a functional group selected from the group consisting of a hydrophilic group, a hydrophobic group, an acidic group, a basic group and an ionic group.

25. The method of claim 13 wherein the functional group is selected from the group consisting of amino, carboxylic acid, sulfide, guanidino, imidazole and hydroxyl groups.

26. The method of claim 15 wherein the modifiable functional group is a protonated amine ionically attached to the biological molecule;

and

wherein the biological molecule is selected from the group consisting of a polynucleotide and a polysaccharide.

27. The method of claim 15 wherein the modifiable functional group is a protonated amine ionically attached to the biological molecule;

and

wherein the biological molecule is heparin.

28. The method of claim 15 wherein the biological molecule alters a chemical or physical property of the graft copolymer.

16. A method of improving the biocompatibility properties of a linear α

-hydroxy-acid polyester backbone having at least one amino acid group incorporated therein, the method comprising;

reacting the polyester with an amino acid derivative thereby to form a poly(amino acid) polymer extending from an amino acid group in the polyester backbone;

wherein the poly(amino acid) includes functional groups capable of altering a chemical or physical property of the polyester.