Hydrogels with covalent and noncovalent crosslinks

• US 8,367,639 B2
• Filed: 06/14/2010
• Issued: 02/05/2013
• Est. Priority Date: 03/31/2005
• Status: Expired due to Fees

• Current Assignee: University of Delaware
• Original Assignee: University of Delaware
• Inventors: Yamaguchi, Nori, Kilck, Kristi L.
• Primary Examiner(s): Jiang, Shaojia Anna
• Assistant Examiner(s): Henry, Michael C
• Application Number:
  US12/814,826
• Publication Number:
  US 20110033543A1
• Time in Patent Office: 967 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 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
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like

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. The hydrogel may contain covalent and non-covalent crosslinks.

Claims

1. A hydrogel comprising a matrix, the matrix comprising a cross-linking structure selected from the group consisting of

(A) PEG-LMWH-PEG,

(B) PEG-LMWH-HBC-LMWH-PEG,

(C) PEG-LMWH-HBC-PEG*-HBC-LMWH-PEG,

(D) PEG-LMWH-PEG-HBC, and

(E) LMWH-PEG-HBC-PEG*;

wherein the hydrogel further comprises a natural or synthetic polymer;

wherein the PEG in a PEG-LMWH conjugate or in a LMWH-PEG conjugate is covalently bound to the LMWH, and is covalently bound to the polymer, and is branched or unbranched;

wherein the HBC is bound to the LMWH molecule by a covalent bond or a non-covalent bond, or wherein the HBC is covalently bound to the PEG molecule in the PEG-LMWH conjugate, or wherein the HBC is covalently bound to a PEG* molecule, wherein the PEG* molecule is a PEG molecule that is not covalently attached to the LMWH, and wherein the PEG* molecule is branched or unbranched.

2. The hydrogel of claim 1, wherein the matrix comprises two or more cross-linking structures selected from (A), (B), (C), (D), and (E).

3. The hydrogel of claim 2, wherein the cross-linking structures are (A) and (B).

4. The hydrogel of claim 2, wherein the cross-linking structures are (A) and (C).

5. The hydrogel of claim 1, wherein the cross-linking structure is (D).

6. The hydrogel of claim 1 wherein the portion of the matrix covalently crosslinked to the polymer is at least 1.5 weight percent.

7. The hydrogel of claim 1 having an elastic modulus of at least 5 Pa.

8. The hydrogel of claim 1 wherein the LMWH molecules are selected from the group consisting of nadroparin, dalteparin, reviparin, ardeparin, enoxaparin, tinzaparin, fondaparinux, parnaparin or certaparin.

9. The hydrogel of claim 1 wherein the heparin-binding compound (HBC) is selected from one or more of growth factors, cytokines, peptides, peptide-modified polymers, proteins, polysaccharides, polysaccharide-modified polymers, peptoids, peptoid-modified polymers and small molecule drugs.

10. The hydrogel of claim 9 wherein the heparin-binding compound (HBC) is a growth factor selected from 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.

11. The hydrogel of claim 1 wherein the heparin-binding compound (HBC) is selected from the group consisting of F56, V1, GU40C4, K237 and QK.

12. The hydrogel of claim 1 wherein the heparin-binding compound (HBC) is selected from PF₄ZIP, RRP, HIP, sHIP and ATIII.