title: Enzymatically-responsive pro-angiogenic peptide-releasing poly(ethylene glycol) hydrogels promote vascularization in vivo.
abstract: Therapeutic angiogenesis holds great potential for a myriad of tissue engineering and regenerative medicine approaches. While a number of peptides have been identified with pro-angiogenic behaviors, therapeutic efficacy is limited by poor tissue localization and persistence. Therefore, poly(ethylene glycol) hydrogels providing sustained, enzymatically-responsive peptide release were exploited for peptide delivery. Two pro-angiogenic peptide drugs, SPARC113 and SPARC118, from the Secreted Protein Acidic and Rich in Cysteine, were incorporated into hydrogels as crosslinking peptides flanked by matrix metalloproteinase (MMP) degradable substrates. In vitro testing confirmed peptide drug bioactivity requires sustained delivery. Furthermore, peptides retain bioactivity with residual MMP substrates present after hydrogel release. Incorporation into hydrogels achieved enzymatically-responsive bulk degradation, with peptide release in close agreement with hydrogel mass loss and released peptides retaining bioactivity. Interestingly, SPARC113 and SPARC118-releasing hydrogels had significantly different degradation time constants in vitro (1.16 and 8.77×10(-2) h(-1), respectively), despite identical MMP degradable substrates. However, upon subcutaneous implantation, both SPARC113 and SPARC118 hydrogels exhibited similar degradation constants of ~1.45×10(-2) h(-1), and resulted in significant ~1.65-fold increases in angiogenesis in vivo compared to controls. Thus, these hydrogels represent a promising pro-angiogenic approach for applications such as tissue engineering and ischemic tissue disorders.
authors.affiliation: Department of Biomedical Engineering, 207 Robert B. Goergen Hall, University of Rochester, Rochester, NY 14627, USA. Electronic address: amy.h.vanhove@rochester.edu.
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. Electronic address: kathleen_Burke@URMC.Rochester.edu.
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. Electronic address: eantonie@u.rochester.edu.
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; Department of Neurobiology and Anatomy, University of Rochester, 601 Elmwood Ave, Rochester, NY, 14642, USA. Electronic address: Edward_Brown@URMC.Rochester.edu.
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. Electronic address: benoit@bme.rochester.edu.
authors.forename: Danielle S W
authors.initials: DS
authors.lastname: Benoit
mesh_terms: D042501:Angiogenic Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry; D002478:Cells, Cultured; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000494:pharmacology; D004337:Drug Carriers / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D006536:Heptanes / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells; D020100:Hydrogels / Q000008:administration & dosage* / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000494:pharmacology; D015676:Osteonectin / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry
chemical_list: C504926:(2.2.1)bicyclohept-2-ene; D042501:Angiogenic Proteins; D001643:Bridged Bicyclo Compounds; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006536:Heptanes; D020100:Hydrogels; D009842:Oligopeptides; D015676:Osteonectin; D011092:Polyethylene Glycols; D020778:Matrix Metalloproteinase 2
keywords: Angiogenesis; Controlled drug release; Enzyme; Hydrogel; Peptide