Temporally Tunable, Enzymatically Responsive Delivery of Proangiogenic Peptides from Poly(ethylene glycol) Hydrogels

Pro-angiogenic drugs hold great potential to promote reperfusion of ischemic tissues and in tissue engineering applications, but efficacy is limited by poor targeting and short half-lives. Methods to control release duration or provide enzymatically-responsive drug delivery have independently improved drug efficacy. However, no material has been developed to temporally control the rate of enzymatically-responsive drug release. To address this void, hydrogels were developed to provide sustained, tunable release of Qk, a pro-angiogenic peptide mimic of vascular endothelial growth factor, via tissue-specific enzymatic activity. After confirmation that sustained delivery of Qk is necessary for pro-angiogenic effects, a variety of previously-identified matrix metalloproteinase (MMP)-degradable linkers were used to tether Qk to hydrogels. Of these, three (IPES↓LRAG, GPQG↓IWGQ, and VPLS↓LYSG) showed MMP-responsive peptide release. These linkers provided tunable Qk release kinetics, with rates ranging from 1.64 to 19.9 × 10−3 hours−1 in vitro and 4.82 to 8.94 × 10−3 hours−1 in vivo. While Qk was confirmed to be bioactive as released, hydrogels releasing Qk failed to induce significant vascularization in vivo after one week, likely due to non-enzymatically degradable hydrogels employed. While Qk was the focus of this study, the approach could easily be adapted to control the delivery of a variety of therapeutic molecules.