title: Temporally tunable, enzymatically responsive delivery of proangiogenic peptides from poly(ethylene glycol) hydrogels.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering 207 Robert B. Goergen Hall, University of Rochester, Rochester, NY, 14627, USA.
authors.forename: Amy H
authors.initials: AH
authors.lastname: Van Hove
authors.affiliation: Department of Biomedical Engineering 207 Robert B. Goergen Hall, University of Rochester, Rochester, NY, 14627, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Antonienko
authors.affiliation: Department of Biomedical Engineering 207 Robert B. Goergen Hall, University of Rochester, Rochester, NY, 14627, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Burke
authors.affiliation: Department of Biomedical Engineering 207 Robert B. Goergen Hall, University of Rochester, Rochester, NY, 14627, USA.|Department of Neurobiology and Anatomy, University of Rochester, 601 Elmwood Ave, Rochester, NY, 14642, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Brown
authors.affiliation: Department of Biomedical Engineering 207 Robert B. Goergen Hall, University of Rochester, Rochester, NY, 14627, USA.|Department of Biomedical Genetics 601 Elmwood Ave, University of Rochester, Rochester, NY, 14642, USA.|Department of Chemical Engineering 206 Gavett Hall, University of Rochester, Rochester, NY, 14627, USA.|Center for Musculoskeletal Research 601 Elmwood Ave, University of Rochester Medical Center, Rochester, NY, 14642, USA.
authors.forename: Danielle S W
authors.initials: DS
authors.lastname: Benoit
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D036641:Microscopy, Fluorescence, Multiphoton; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012867:Skin / Q000098:blood supply / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000494:pharmacology
chemical_list: D020100:Hydrogels; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D011092:Polyethylene Glycols; D020782:Matrix Metalloproteinases; D016650:Fluorescein-5-isothiocyanate
keywords: drug delivery; hydrogels; stimuli-responsive materials; temporal control; therapeutic peptides