Targeted Delivery and Controlled Release of a Small Molecule Matrix Metalloproteinase Inhibitor Using a Self-Assembling Hydrogel Following Myocardial Infarction

Abstract

Background Strategic delivery of biomaterials to the newly formed myocardial infarction (MI) continues to be an area of active investigation and offers the opportunity to reappraise the use of small molecule therapeutics that hold high target specificity but are problematic when systemically delivered. The goal of this study was to examine the effects of late post-MI delivery (3 days post-MI) of a self-assembling hydrogel (SAgel), which had been loaded with a previously characterized matrix metalloproteinase inhibitor (MMPi). Hypothesis Using a minimally invasive (mini-thoracotomy) and an SAgel allowing for targeted myocardial injection array within the MI region of a large animal model as well as localized release of an MMPi, improved LV function and geometry would be demonstrated up to 28 days post-MI. Methods and Results MI was induced in adult pigs (25 kg) by left anterior descending (LAD) catheter balloon occlusion (90 min/then reperfusion) and at 3 days post-MI randomized to MI-SAgel/SD7300 (500 μg/mL; n=7) or saline (MI saline; n=8), whereby the injections were performed in a 9 point 100 uL array within the targeted LAD region. The SAgel adapts fluid-like properties to flow through the syringe (21 Gauge) due to shear forces during injection and rapidly reassembles with encapsulated SD7300 following injection into the MI region. LV ejection fraction (LVEF) and end-diastolic volume (LVEDV) were measured at Baseline (pre-MI) and at 14 and 28 days post-MI by echocardiography. LVEF fell post-MI but was significantly attenuated by SAgel/SD7300 injections. LVEDV increased from Baseline (35±2 mL) in the MI-saline (84+6) and MI-SAgel/SD7300 (64+4 mL groups at 28 days post-MI (p Conclusions This is the first study to demonstrate the feasibility of targeted delivery of a self-assembling injectable gel using a minimally invasive surgical approach at a relevant post-MI time point. Second, targeted delivery of this gel containing an MMPi for sustained local release demonstrated sustained beneficial effects on post-MI remodeling.