Biodegradable polymers for cell transplantation

• US 5,399,665 A
• Filed: 11/05/1992
• Issued: 03/21/1995
• Est. Priority Date: 11/05/1992
• Status: Expired due to Term

• Current Assignee: Children's Medical Center Corporation, Massachusetts Institute of Technology
• Original Assignee: Children's Hospital, Massachusetts Institute of Technology
• Inventors: Barrera, Denise, Langer, Robert S., Vacanti, Joseph P., Lansbury, Peter T. Jr.
• Primary Examiner(s): Acquah, Samuel A.
• Assistant Examiner(s): Dodson, Shelley A.
• Application Number:
  US07/972,156
• Time in Patent Office: 866 Days
• Field of Search: 424/426, 424/486, 424/484, 424/78.19, 435/180, 435/181, 435/182, 528/271, 528/354, 528/357, 528/361, 530/815, 514/1, 514/2
• US Class Current: 528/354
• CPC Class Codes: A61K 47/593 Polyesters, e.g. PLGA or polylactide-co-glycolide
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61L 2300/25 Peptides having up to 20 amino acids in a defined sequence
• CPC Class Codes: A61L 2300/604 Biodegradation
• CPC Class Codes: A61L 2300/64 Animal cells
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3804 characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C07K 14/001 by chemical synthesis
• CPC Class Codes: C08G 63/6852 derived from hydroxy carboxylic acids
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence
• CPC Class Codes: C12N 2533/40 Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06
• CPC Class Codes: Y10S 530/815 Carrier is a synthetic polymer

Abstract

Polymers more suitable for use in organ transplantation are formed by coupling biologically active moieties to the free amino groups of polymers formed by incorporation of α amino acids into polymers formed of alpha hydroxy acids such as lactic acids. In the preferred embodiment, the peptides are coupled to the free amino groups.

Claims

1. a biodegradable, biocompatible polymer formed by polymerizing a morpholinedione, wherein the morpholinedione is a dimer of

(i) an α

-hydroxy acid of the formula R, R'"'"'--COH--CO--OH wherein R and R'"'"' are independently H or a linear or branched alkyl; and

(ii) an α

-amino acid of the formula R", R"'"'"'--CNH₂ --CO--OH wherein R" and R"'"'"' are independently H or a linear or branched alkyl;

a protected primary or secondary amino group;

a protected ester;

a protected hydroxyl;

a protected sulfide;

a protected amide;

a protected guanidino;

or a protected imidazole.

2. The polymer of claim 1 wherein the α

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

3. The polymer of claim 1 wherein the amino acid is N-e-protected lysine.

4. The polymer of claim 1 wherein biologically active moieties are coupled to free carboxylic acids, amino groups, sulfide groups, guanidino, imidazole or hydroxyl groups on the amino acids.

5. The polymer of claim 4 wherein the biologically active moieties are selected from the group consisting of GRGDY, YIGSR and other RGD peptides.

8. The process of claim 1 wherein the amino acid is N-e-protected lysine.

9. The process of claim 1 further comprising coupling biologically active moieties to free carboxylic acids, amino groups, sulfide groups, guanidino, imidazole or hydroxyl groups on the amino acids.

10. The process of claim 9 wherein the biologically active moleties are selected from the group consisting of GRGDY, YIGSR and other RGD peptides.

11. The process of claim 9 further comprising forming the polymer into a matrix for seeding with cells.

12. The process of claim 11 further comprising seeding the matrix with cells.

20. The biocompatible biodegradable polymer of claim 1 further comprising biologically active moieties chemically coupled to the polymer.

21. The polymer of claim 20 wherein the biologically active moieties are attachment peptides.

22. The polymer of claim 1 wherein the protecting groups on the α

-amino acid are deprotected.

6. A process for making a biocompatible, biodegradable polymer comprising:

(A) forming a morpholinedione by chemically coupling

(i) an α

-amino acid of the formula R", R"'"'"'--CNH₂ --CO--OH, wherein R" and R"'"'"' are independently H or a linear or branched alkyl;

a protected primary or secondary amino group;

a protected ester;

a protected hydroxyl;

a protected sulfide;

a protected amide;

a protected guanidino;

or a protected imidazole; and

(ii) an α

-hydroxy acid of the formula R,R'"'"'--COH--CO--OH, wherein R and R'"'"' are independently H or a linear or branched alkyl; and

(B) polymerizing the morpholinedione with a Lewis acid.

7. The process of claim 6 wherein the α

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

23. The method of claim 6 further comprising deprotecting the protecting groups on the α

-amino acid.

13. A method for implanting cells into an animal comprising

(A) forming a matrix of a biocompatible, biodegradable polymer formed by polymerizing a morpholinedione wherein the morpholinedione is a dimer of

(i) an α

-hydroxy acid of the formula R,R'"'"'--COH--CO--OH, wherein R and R'"'"' are independently H or a linear or branched alkyl; and

(ii) an α

-amino acid of the formula R",R"'"'"'--CNH₂ --CO--OH, wherein R" and R"'"'"' are independently H or a linear or branched alkyl;

a protected primary or secondary amino group;

a protected ester;

a protected hydroxyl;

a protected sulfide;

a protected amide;

a protected guanidino;

or a protected imidazole, and

(B) seeding the matrix with cells.

14. The method of claim 13 further comprising deprotecting protected amino, ester, hydroxyl, sulfide, amide, guanidino or imidazole groups on the polymer, and coupling biologically active moieties to free carboxylic acid, amino groups, sulfide groups, guanidino, imidazole or hydroxyl groups on the amino acids.

15. The process of claim 13 wherein the α

-hydroxy acids are selected from the group consisting of lactic acid and glycolic acid.

16. The process of claim 13 wherein the amino acid is lysine.

17. The process of claim 13 wherein the biologically active moieties are selected from the group consisting of GRGDY, YIGSR and other RGD peptides.

18. The process of claim 13 wherein the cells are selected from the group consisting of hepatocytes, pancreatic cells, intestinal cells, uroendothelial cells, skin cells, muscle cells, nerve cells, and bone cells.

19. The process of claim 13 further comprising implanting the matrix seeded with cells.