Controlled release of growth factors and signaling molecules for promoting angiogenesis

• US 9,539,309 B2
• Filed: 04/06/2015
• Issued: 01/10/2017
• 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:
  US14/679,723
• Publication Number:
  US 20150283210A1
• Time in Patent Office: 645 Days
• Field of Search: None
• US Class Current: 1/1
• 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 wherein increased blood supply is needed.

Claims

1. A device comprising an alginate hydrogel scaffold composition comprising N—

[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and a vascular endothelial growth factor (VEGF), wherein the VEGF comprises VEGF₁₂₁, VEGF₁₄₅, VEGF₁₆₅, VEGF₁₈₉, or VEGF₂₀₆, and wherein the alginate hydrogel scaffold composition temporally controls the release of the DAPT and the VEGF from the alginate hydrogel scaffold composition.

2. The device of claim 1, wherein the DAPT is released from the alginate hydrogel scaffold composition at a first rate and the VEGF is released from the alginate hydrogel scaffold composition at a second rate, and wherein the second rate is slower than the first rate.

3. The device of claim 1, wherein the VEGF is covalently linked to the alginate hydrogel scaffold composition.

4. The device of claim 1, wherein the VEGF is non-covalently linked to the alginate hydrogel scaffold composition.

5. The device of claim 1, wherein the scaffold composition degrades at a predetermined rate based on a physical parameter selected from the group consisting of temperature, pH, hydration status, and porosity.

6. The device of claim 1, wherein the DAPT is released before the VEGF from the alginate hydrogel scaffold composition.

7. The device of claim 1, wherein the alginate hydrogel scaffold composition comprises nanopores.

8. The device of claim 1, wherein the DAPT is released from the alginate hydrogel scaffold composition within 1 to 3 days.

9. The device of claim 1, wherein the VEGF is released from the alginate hydrogel scaffold composition within 7 to 60 days.

10. The device of claim 1, wherein the alginate hydrogel scaffold composition comprises a molar ratio of 1:

1 to 1;

200 for VEGF₁₆₅ to DAPT.

11. The device of claim 1, wherein the alginate hydrogel scaffold composition comprises a molar ratio of 1:

31 for VEGF₁₆₅ to DAPT.

12. The device of claim 1, wherein the alginate hydrogel scaffold composition further comprises platelet-derived growth factor (PDGF).

13. The device of claim 12, wherein the PDGF comprises PDGF-BB.

14. The device of claim 13, wherein the alginate hydrogel scaffold composition comprises a molar ratio of 1:

1 to 1;

200 for PDGF-BB to DAPT.

15. The device of claim 14, wherein the alginate hydrogel scaffold composition comprises a molar ratio of 1.8:

31 for PDGF-BB to DAPT.