Targeted Treatment of Ischemic and Fibrotic Complications of Myocardial Infarction Using a Dual-Delivery Microgel Therapeutic

Myocardial infarction (MI), commonly known as a heart attack, affects millions of people worldwide and results in significant death and disabilities. A major cause of MI is fibrin-rich thrombus formation that occludes the coronary arteries, blocking blood flow to the heart and causing fibrin deposition. In treating MI, re-establishing blood flow is critical. However, ischemia reperfusion (I/R) injury itself can also occur and contributes to cardiac fibrosis. Fibrin-specific poly­(<i>N</i>-isopropylacrylamide) nanogels (FSNs) comprised of a core–shell colloidal hydrogel architecture are utilized in this study to design a dual-delivery system that simultaneously addresses the need to (1) re-establish blood flow and (2) inhibit cardiac fibrosis following I/R injury. These therapeutic needs are met by controlling the release of a fibrinolytic protein, tissue plasminogen activator (tPA), and a small molecule cell contractility inhibitor (Y-27632). <i>In vitro</i>, tPA and Y-27632-loaded FSNs rapidly degrade fibrin and decrease cardiac cell stress fiber formation and connective tissue growth factor expression, which are both upregulated in cardiac fibrosis. <i>In vivo</i>, FSNs localize to fibrin in injured heart tissue and, when loaded with tPA and Y-27632, showed significant improvement in left ventricular ejection fraction 2 and 4 weeks post-I/R as well as significantly decreased infarct size, α-smooth muscle actin expression, and connective tissue growth factor expression 4 weeks post-I/R. Together, these data demonstrate the feasibility of this targeted therapeutic strategy to improve cardiac function following MI