BME Ph.D. Thesis Defense Seminar
Tuesday, April 7, 2015
Goergen Hall 101 (Sloan Auditorium)
“Enzymatically-responsive Poly(ethylene glycol) Hydrogels for the Controlled Delivery of Therapeutic Peptides”
Presented by: Amy H. Van Hove
Supervised by: Professor Danielle Benoit
Abstract: Therapeutic angiogenesis holds great potential for treatment of ischemic tissues and in tissue engineering, where insufficient vascularization limits construct size, complexity, and anastomosis with host vasculature. However, no FDA approved treatments exist to robustly enhance vascularization within ischemic tissue. Many pro-angiogenic approaches have been developed, often via delivery of angiogenic proteins or peptides. Peptides typically mimic the bioactivity of larger proteins or growth factors, and offer advantages over traditional protein delivery. However, like proteins, peptides suffer from rapid clearance and poor pharmacokinetics when delivered systemically. Therefore, a poly(ethylene glycol) (PEG) hydrogel-based platform technology was developed to control and sustain peptide drug release via matrix metalloproteinase (MMP) activity.
In vitro bioactivity testing identified three peptides (Qk (from Vascular Endothelial Growth Factor), SPARC113, and SPARC118 (from Secreted Protein Acidic and Rich in Cysteine)) that retained bioactivity in their expected released forms (e.g., with residual amino acids left by MMP substrates after cleavage). Incorporation of these peptides into hydrogels flanked by MMP-degradable substrates successfully produced hydrogels with enzymatically-responsive hydrogel degradation and peptide release behaviors. Qk, SPARC113, and SPARC118-releasing hydrogels were confirmed to release bioactive components in vitro after MMP-mediated degradation. Further investigation revealed key peptide drug properties, specifically size and hydrophobicity, control the rate of hydrogel degradation and peptide release. When implanted subcutaneously, SPARC113 and SPARC118-releasing hydrogels both significantly increased vascular ingrowth compared to controls without significantly affecting vessel size. As the longitudinal availability of VEGF has been shown critical for bioactivity, alternate hydrogels were developed to provide temporal control over enzymatically-responsive release of Qk, the VEGF peptide mimic. Modifying the MMP-degradable linker used to tether Qk to hydrogels provided temporal control over enzymatically-responsive peptide release in vitro and in vivo. Qk was confirmed to be bioactive as released, but hydrogels releasing Qk failed to induce significant vascularization in vivo, likely due to use of non-degradable hydrogels. The hydrogels developed represent promising pro-angiogenic therapies, and can be easily adapted to control release of a variety of therapeutic molecules.