title: Development and in vitro assessment of enzymatically-responsive poly(ethylene glycol) hydrogels for the delivery of therapeutic peptides.
abstract: Despite the recent expansion of peptide drugs, delivery remains a challenge due to poor localization and rapid clearance. Therefore, a hydrogel-based platform technology was developed to control and sustain peptide drug release via matrix metalloproteinase (MMP) activity. Specifically, hydrogels were composed of poly(ethylene glycol) and peptide drugs flanked by MMP substrates and terminal cysteine residues as crosslinkers. First, peptide drug bioactivity was investigated in expected released forms (e.g., with MMP substrate residues) in vitro prior to incorporation into hydrogels. Three peptides (Qk (from Vascular Endothelial Growth Factor), SPARC113, and SPARC118 (from Secreted Protein Acidic and Rich in Cysteine)) retained bioactivity and were used as hydrogel crosslinkers in full MMP degradable forms. Upon treatment with MMP2, hydrogels containing Qk, SPARC113, and SPARC118 degraded in 6.7, 6, and 1 days, and released 5, 8, and, 19% of peptide, respectively. Further investigation revealed peptide drug size controlled hydrogel swelling and degradation rate, while hydrophobicity impacted peptide release. Additionally, Qk, SPARC113, and SPARC118 releasing hydrogels increased endothelial cell tube formation 3.1, 1.7, and 2.8-fold, respectively. While pro-angiogenic peptides were the focus of this study, the design parameters detailed allow for adaptation of hydrogels to control peptide release for a variety of therapeutic applications.
authors.affiliation: Department of Biomedical Engineering, 308 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 Genetics, 601 Elmwood Ave, University of Rochester, Rochester, NY 14642, USA. Electronic address: michael-john_beltejar@urmc.rochester.edu.
authors.forename: Michael-John G
authors.initials: MJ
authors.lastname: Beltejar
authors.affiliation: Department of Biomedical Engineering, 308 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: D000595:Amino Acid Sequence; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism*
chemical_list: D003692:Delayed-Action Preparations; D020100:Hydrogels; D010455:Peptides; D011092:Polyethylene Glycols; D020782:Matrix Metalloproteinases
keywords: Controlled drug release; Enzymatically degradable; Hydrogel; Matrix metalloproteinase; Peptide