Controlled Release of Growth Factors and Signaling Molecules for Promoting Angiogenesis

• US 20110117170A1
• Filed: 06/01/2009
• Published: 05/19/2011
• 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.
• Granted Patent: US 9,012,399 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• 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 purposed promoting angiogenesis in target tissues.

Claims

1. A device comprising a scaffold composition, a bioactive composition, and a regulatory agent, said bioactive composition and said regulatory agent being incorporated into or coated onto said scaffold composition, wherein said regulatory agent controls the activity of said bioactive agent.

2. The device of claim 1, wherein said bioactive composition is released from said scaffold composition at a first rate and said regulatory agent is released from said scaffold composition at a second rate.

3. The device of claim 1, wherein said bioactive composition is a pro-angiogenic factor and said regulatory agent is an inhibitor or enhancer of angiogenesis.

4. The device of claim 1, wherein said bioactive composition is a vascular endothelial growth factor (VEGF) or a platelet derived growth factor (PDGF).

5. The device of claim 1, wherein said regulatory agent is a Notch inhibitor.

6. The device of claim 1, wherein said Notch inhibitor is N—

[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT).

7. The device of claim 1, wherein said device comprises a molar ratio of 1:

1 to 1;

200 for VEGF₁₆₅ to DAPT, 1;

1 to 1;

200 for PDGF-BB to DAPT, and 1;

0.1;

1 to 1;

10;

200 for VEGF₁₆₅, PDGF-BB and DAPT, in an alginate polymer scaffold.

8. The device of claim 1, wherein said device comprises a molar ratio of 1:

31 for VEGF₁₆₅ to DAPT, 1.8;

31 for PDGF to DAPT, and 1;

1.8;

31 for VEGF₁₆₅;

PDGF-BB;

DAPT.

9. The device of claim 1, wherein said bioactive composition is covalently linked to said scaffold composition.

10. The device of claim 1, wherein said bioactive composition is non-covalently linked to said scaffold composition.

11. The device of claim 3, wherein said pro-angiogenic factor is selected from the group consisting of ligands including endothelial growth factor (VEGF (A-F)), fibroblast growth factors (acidic and basic FGF 1-10), granulocyte-macrophage colony-stimulating factor (GM-CSF), insulin, insulin growth factor or insulin-like growth factor (IGF), insulin growth factor binding protein (IGFBP), placenta growth factor (PIGF), angiopoietin (Ang1 and Ang2), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), transforming growth factor (TGF-α

, TGF-β

, isoforms 1-3), platelet-endothelial cell adhesion molecule-1 (PECAM-1), vascular endothelial cadherin (VE-cadherin), nitric oxide (NO), chemokine (C—

X—

C motif) ligand 10 (CXCL10) or IP-10, interleukin-8 (IL-8), hypoxia inducible factor (HIF), monocyte chemotactic protein (MCP), vascular cell adhesion molecule (VCAM), ephrin ligands (including Ephrin-B2 and -B4);

transcription factors including HIF-1α

, HIF-1β and

HIF-2α

, Ets-1, Hex, Vezf1, Hox, GATA, LKLF, COUP-TFII, Hox, MEF2, Braf, Prx-1, Prx-2, CRP2/SmLIM and GATA family members, basic helix-loop-helix factors and their inhibitors of differentiation; and

regulatory molecules including enzymes (matrix metalloproteinase (MMP), tissue plasminogen activator (PLAT or tPA), cyclooxygenase (COX), angiogenin).

12. The device of claim 1, wherein said regulatory agent comprises a signaling molecule.

13. The device of claim 12, wherein said signaling molecule is selected from the group consisting of monoclonal antibodies to Notch ligands and/or receptors, RNA interference of Notch ligands or receptors, antisense Notch, receptor and mastermind-like 1 (MAML1) decoys, beta and gamma-secretase inhibitors (GSI), and a molecule that activates or inhibits Notch signaling.

14. The device of claim 13, wherein said GSI is N—

[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT).

15. 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.

16. The device of claim 1, wherein said scaffold composition is enzymatically digested by a composition elicited by a contacting cell, said release of said bioactive composition being dependent upon the rate of enzymatic digestion.

17. 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 with a device comprising a scaffold composition with a bioactive composition and a regulatory agent being incorporated therein or thereon and contacting a mammalian tissue with said device, wherein said scaffold composition temporally controls release of said bioactive composition and wherein said bioactive composition induces angiogenesis, arteriogenesis, or vasculogenesis.

18. The method of claim 17, wherein said bioactive composition comprises VEGF or PDGF and wherein said regulatory agent comprises DAPT.

19. The method of claim 17, where in said bioactive composition is released over a period of weeks and said regulatory agent is released of a period of less than one week.

20. The method of claim 17, wherein a release rate of said regulatory agent is 7-20 fold shorter than that of said bioactive composition.

21. The method of claim 20, wherein said regulatory agent comprises a Notch inhibitor and said bioactive composition comprises VEGF or PDGF.

22. The method of claim 21, wherein said Notch inhibitor is released within 1-3 days and said VEGF or PDGF is released within 7-60 days.

23. The method of claim 17, wherein said mammal is a human.

24. The method of claim 17, wherein said scaffold composition is administered by injection, endoscopic delivery, minimally invasive delivery, or surgical implantation.