Controlled release of growth factors and signaling molecules for promoting angiogenesis

• US 9,012,399 B2
• Filed: 06/01/2009
• Issued: 04/21/2015
• Est. Priority Date: 05/30/2008
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Cao, Lan, Mooney, David J.
• Primary Examiner(s): Allen, Marianne P
• Application Number:
  US12/992,617
• Publication Number:
  US 20110117170A1
• Time in Patent Office: 2,150 Days
• Field of Search: None
• US Class Current: 514/8.1
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/1858 Platelet-derived growth factor [PDGF]
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 2300/412 Tissue-regenerating or healing or proliferative agents
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/432 Inhibitors, antagonists A61L2300/402 - A61L2300/43 take precedence
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The present invention comprises compositions, methods, and devices for delivering angiogenic factors and signaling molecules to a target tissue, and controlling the release of these factors and signaling molecules to spatially and temporally restrict their release and dissemination, for the purpose of promoting angiogenesis in target tissues.

Claims

1. A method of inducing growth of new blood vessels either from existing blood vessels, or creation of de novo vessels, or a combination thereof, in a target tissue of a mammal, comprising contacting a mammalian cell by injecting into a tissue a device comprising an alginate hydrogel scaffold composition comprising N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and vascular endothelial growth factor (VEGF), wherein said scaffold composition temporally controls release of the DAPT and the VEGF, wherein the VEGF said bioactive composition induces angiogenesis, arteriogenesis, or vasculogenesis, and wherein the VEGF comprises VEGF₁₂₁, VEGF₁₄₅, VEGF₁₆₅, VEGF₁₈₉, or VEGF₂₀₆.

2. The method of claim 1, wherein the DAPT is released before the VEGF.

3. The method of claim 1, wherein said VEGF is released over a period of weeks and said DAPT is released over a period of less than one week.

4. The method of claim 1, wherein said mammal is a human.

5. The method of claim 1, wherein said mammal has diabetes.

6. The method of claim 1, wherein said hydrogel scaffold comprises nanopores.

7. The method of claim 1, wherein the DAPT is released from the scaffold composition at a first rate and the VEGF is released from the scaffold composition at a second rate, and wherein the second rate is slower than the first rate.

8. The method of claim 7, wherein the VEGF exits from the scaffold composition for a time period of one or more weeks.

9. The method of claim 7, wherein the DAPT exits from the scaffold composition for a period of one or more days.

10. The method of claim 1, wherein the device comprises a molar ratio of 1:

1 to 1;

200 for VEGF₁₆₅ to DAPT.

11. The method of claim 10, wherein the device comprises a molar ratio of 1:

31 for VEGF₁₆₅ to DAPT.

12. The method of claim 1, wherein the mammal has coronary arterial disease (CAD) or peripheral arterial disease (PAD).

13. The method of claim 1, wherein the mammal has acute or chronic ischemia due to peripheral arterial disease (PAD).

14. The method of claim 1, wherein the mammal has a diabetic ulcer or a wound due to peripheral arterial disease (PAD).

15. A method of inducing growth of new blood vessels either from existing blood vessels, or creation of de novo vessels, or a combination thereof, in a target tissue of a mammal, comprising contacting a mammalian cell by injecting into a tissue a device comprising an alginate hydrogel scaffold composition comprising N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and a bioactive composition selected from the group consisting of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), wherein said scaffold composition temporally controls release of the DAPT and the bioactive composition, wherein the bioactive composition induces angiogenesis, arteriogenesis, or vasculogenesis, and wherein the VEGF comprises VEGF₁₂₁, VEGF₁₄₅, VEGF₁₆₅, VEGF₁₈₉, or VEGF₂₀₆.

16. The method of claim 15, wherein said DAPT is released within 1-3 days and said VEGF or PDGF is released within 7-60 days.

17. The method of claim 15, wherein the DAPT is released before the bioactive composition.

18. The method of claim 15, wherein the PDGF comprises PDGF-BB.

19. The method of claim 15, wherein the device comprises a molar ratio of 1:

1 to 1;

200 for VEGF₁₆₅ to DAPT, or 1;

1 to 1;

200 for PDGF-BB to DAPT.

20. The method of claim 19, wherein the device comprises a molar ratio of 1.8:

31 for PDGF-BB to DAPT.

21. The method of claim 15, wherein the mammal has coronary arterial disease (CAD) or peripheral arterial disease (PAD).

22. The method of claim 15, wherein the mammal has acute or chronic ischemia due to peripheral arterial disease (PAD).

23. The method of claim 15, wherein the mammal has a diabetic ulcer or a wound due to peripheral arterial disease (PAD).

24. A method of inducing growth of new blood vessels either from existing blood vessels, or creation of de novo vessels, or a combination thereof, in a target tissue of a mammal, comprising contacting a mammalian cell by injecting into a tissue a device comprising a hydrogel scaffold composition comprising N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), wherein said scaffold composition temporally controls release of the DAPT, VEGF, and PDGF, and wherein the VEGF and PDGF induce angiogenesis, arteriogenesis, or vasculogenesis.

25. The method of claim 24, wherein the device comprises a molar ratio of 1:

0.1;

1 to 1;

10;

200 for VEGF₁₆₅, PDGF-BB and DAPT.

26. The method of claim 25, wherein the device comprises a molar ratio of 1:

1.8;

31 for VEGF₁₆₅, PDGF-BB and DAPT.

27. The method of claim 24, wherein the mammal has coronary arterial disease (CAD) or peripheral arterial disease (PAD).

28. The method of claim 24, wherein the mammal has acute or chronic ischemia due to peripheral arterial disease (PAD).

29. The method of claim 24, wherein the mammal has a diabetic ulcer or a wound due to peripheral arterial disease (PAD).