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

• Published in: Advanced healthcare materials 2015-09, Vol.4 (13), p.2002-2011
• Main Authors: Van Hove, Amy H., Antonienko, Erin, Burke, Kathleen, Brown III, Edward, Benoit, Danielle S. W.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biocompatibility; Crosslinking; Degradation; drug delivery; Drug delivery systems; Drugs; Female; Fluorescein-5-isothiocyanate - chemistry; Glycols; Human Umbilical Vein Endothelial Cells; Humans; Hydrogels; Hydrogels - chemistry; Matrix Metalloproteinases - metabolism; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Microscopy, Fluorescence, Multiphoton; Molecular Sequence Data; Neovascularization, Physiologic - drug effects; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Polyethylene Glycols - chemistry; Skin - blood supply; Skin - pathology; stimuli-responsive materials; Surgical implants; temporal control; therapeutic peptides; Vascular Endothelial Growth Factor A - chemistry; Vascular Endothelial Growth Factor A - pharmacology
• ISSN: 2192-2640; 2192-2659
• DOI: 10.1002/adhm.201500304

Proangiogenic 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 are developed to provide sustained, tunable release of Qk, a proangiogenic peptide mimic of vascular endothelial growth factor, via tissue‐specific enzymatic activity. After confirmation that sustained delivery of Qk is necessary for proangiogenic effects, a variety of previously identified matrix metalloproteinase (MMP)‐degradable linkers are used to tether Qk to hydrogels. Of these, three (IPES↓LRAG, GPQG↓IWGQ, and VPLS↓LYSG) show MMP‐responsive peptide release. These linkers provide tunable Qk release kinetics, with rates ranging from 1.64 to 19.9 × 10−3 h−1 in vitro and 4.82 to 8.94 × 10−3 h−1 in vivo. While Qk is confirmed to be bioactive as released, hydrogels releasing Qk fail to induce significant vascularization in vivo after one week, likely due to the use of nonenzymatically degradable hydrogels. While Qk is the focus of this study, the approach could easily be adapted to control the delivery of a variety of therapeutic molecules. Temporal control over enzymatically responsive peptide delivery from poly(ethylene glycol) hydrogels. Multiarm norbornene functionalized poly(ethylene glycol) is partially cross‐linked with enzymatically stable cross‐linking peptides. The remaining norbornene groups are linked to the therapeutic peptide Qk (blue ovals) via varying enzymatically degradable peptide tethers, which provide temporal control over enzymatically responsive peptide release.