Cell-mediated delivery and targeted erosion of noncovalently crosslinked hydrogels

• US 8,415,325 B2
• Filed: 06/14/2010
• Issued: 04/09/2013
• Est. Priority Date: 03/31/2005
• Status: Active Grant

• Current Assignee: University of Delaware
• Original Assignee: University of Delaware
• Inventors: Kiick, Kristi L., Yamaguchi, Nori
• Primary Examiner(s): Jiang, Shaojia Anna
• Assistant Examiner(s): Henry, Michael C
• Application Number:
  US12/814,767
• Publication Number:
  US 20100317110A1
• Time in Patent Office: 1,030 Days
• Field of Search: 514/56, 514/54, 514/23, 514/2, 536/21, 424/488, 424/486
• US Class Current: 514/56
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/70 Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug hollow drug-filled fibres A61K9/0092

Abstract

A method for targeted delivery of therapeutic compounds from hydrogels is presented. The method involves administering to a cell a hydrogel in which a therapeutic compound is noncovalently bound to heparin.

Claims

1. A method for delivery of a heparin-binding therapeutic compound to a target cell, the method comprising administering in vivo a hydrogel comprising a heparin-binding therapeutic compound capable of receptor-mediated binding to a surface of the target cell;

wherein the hydrogel further comprises a cross-linked matrix comprising at least two polymer-LMWH conjugates, wherein the polymer comprises PEG and wherein the polymer of at least one of the polymer-LMWH conjugates is covalently bound to at least one LMWH molecule; and

wherein a fraction of the polymer-LMWH conjugates is noncovalently bound to the heparin-binding therapeutic compound.

2. The method of claim 1, wherein the heparin-binding therapeutic compound is a growth factor.

3. The method of claim 2, wherein the growth factor is selected from the group consisting of vascular endothelial growth factor, basic fibroblast growth factor, acidic fibroblast growth factor, heparin-binding epidermal growth factor, transforming growth factor-beta, and nerve growth factor.

4. The method of claim 1, wherein the heparin-binding therapeutic compound is selected from the group consisting of a polymer covalently modified with a peptide, a polymer covalently modified with a polysaccharide, peptides, proteins, polysaccharides, peptoids, and small molecule drugs.

5. The method of claim 1, wherein the heparin-binding therapeutic compound is a growth factor agonist or antagonist capable of binding heparin.

6. The method of claim 5, wherein the heparin-binding therapeutic compound is selected from the group consisting of F56, V1, GU40C4, K237, and QK.

7. The method of claim 1, wherein the heparin-binding therapeutic compound is released from the hydrogel in the presence of a cell capable of receptor-mediated binding to the heparin-bindinq therapeutic compound.

8. The method of claim 7, wherein release of the heparin-binding therapeutic compound from the hydrogel stimulates erosion of the hydrogel.

9. The method of claim 1, wherein the rate of release of the heparin-binding therapeutic compound is regulated by the heparin-binding affinity of the heparin-binding therapeutic compound.

10. The method of claim 4, wherein the polymer covalently modified with a peptide comprises a peptide selected from the group consisting of SEQ ID NO:

4, 5, 6, and 7.

11. The method of claim 1, wherein the polymer of each polymer-LMWH conjugate is covalently crosslinked to a polymer matrix.