Effects of Molecular Weight and Loading on Matrix Metalloproteinase-2 Mediated Release from Poly(Ethylene Glycol) Diacrylate Hydrogels

Abstract

Herein, we report on continued efforts to understand an implantable poly(ethylene glycol) diacrylate (PEGDA) hydrogel drug delivery system that responds to extracellular enzymes, in particular matrix metalloproteinase-2 (MMP-2) to provide controlled drug delivery. By attaching peptide as pendant groups on the hydrogel backbone, drug release occurs at an accelerated rate in the presence of active protease. We investigated MMP-2 entry and optimized parameters of the drug delivery system. Mesh size for different PEGDA molecular weight macromers was measured with PEGDA 3,400 hydrogels having a mesh size smaller than the dimensions of MMP-2 and PEGDA 10,000 and PEGDA 20,000 hydrogels having mesh sizes larger than MMP-2. Purified MMP-2 increased release of peptide fragment compared to buffer at several loading concentrations. Cell-stimulated release was demonstrated using U-87 MG cells embedded in collagen. GM6001, an MMP inhibitor, diminished release and altered the identity of the released peptide fragment. The increase in ratio of release from PEGDA 10,000 and PEGDA 20,000 hydrogels compared to PEGDA 3,400 hydrogels suggests MMP-2 enters the hydrogel. PEGDA molecular weight of 10,000 and 15 % (w/V) were the optimal conditions for release and handling. The use of protease-triggered drug delivery has great advantage particularly with the control of protease penetration as a parameter for controlling rate of release.