Hydrogels with covalent and noncovalent crosslinks
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.
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 PF 4 ZIP, RRP, HIP, sHIP and ATIII.