Development and in vitro assessment of enzymatically-responsive poly(ethylene glycol) hydrogels for the delivery of therapeutic peptides.
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.
['Van Hove|Amy H|AH|', 'Beltejar|Michael-John G|MJ|', 'Benoit|Danielle S W|DS|']
D000595:Amino Acid Sequence D003692:Delayed-Action Preparations D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D020100:Hydrogels D020782:Matrix Metalloproteinases D008958:Models, Molecular D008969:Molecular Sequence Data D010455:Peptides D011092:Polyethylene Glycols
Hydrogel Peptide Matrix metalloproteinase Controlled drug release Enzymatically degradable