Abstract 11376: Catheter-Injectable Hydrogel for the Delivery of a Minicircle Encoding SDF-la as Therapy for Myocardial Infarction

Abstract

Myocardial infarction ( MI ) is a leading cause of cardiovascular disease in the U.S. and abroad. Transient delivery of stromal cell-derived factor 1 ( SDF-1 α ) either through the delivery of protein-encoding genes or the protein itself has demonstrated improved cardiac function in preclinical models. However, the delivery of the therapy suffers from two limitations: (1) poor retention when injected into the contracting myocardium, and (2) rapid degradation of the protein, which requires prolonged activity to be therapeutically effective. To mitigate these limitations, we developed a catheter-injectable gel to deliver SDF-1 α encoding minicircles ( MC ). Design of gels for injection into the myocardium is historically challenging since traditional chemical strategies result in gels that are either too stiff and not catheter injectable or too weak and quickly ejected out of the contracting heart muscle. To address this challenge, our approach is to use dynamic covalent chemical (DCC) bonds, which are mechanically strong yet reversible, resulting in a shear-thinning gel (hence catheter injectable) and self-healing (hence retained in the contracting heart muscle). This biocompatible gel is chemically defined for future FDA approval and is synthesized from completely biodegradable polymers: recombinant elastin-like protein and hyaluronic acid. Rheological characterization identified several gel formulations that were easily extruded through a catheter (2 m long and .25 mm internal diameter) and rapidly reformed into a gel within 5 seconds after extrusion. To demonstrate the potential for clinical translatability, we evaluated the injectability and retention of the gel within the contracting rat myocardium. Our gel significantly improved the retention of a microparticle cargo by 200% compared to delivery in Matrigel. Current work is focused on evaluating the therapeutic efficacy of the gel in a rat myocardial infarct model when delivering a therapeutic cargo of SDF-1a-encoding MC. This biocompatible, catheter-injectable gel has great potential to significantly improve the delivery and retention of therapeutic cargo within mechanically active tissues, significantly improving the prolonged efficacy of MI therapies.