Targeted Treatment of Ischemic and Fibrotic Complications of Myocardial Infarction Using a Dual-Delivery Microgel Therapeutic.
ACS Nano. 2018 Jul 17;:
Authors: Mihalko E, Huang K, Sproul E, Cheng K, Brown AC
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, reestablishing blood flow is critical. However, ischemia reperfusion (I/R) injury itself can also occur and contributes to cardiac fibrosis. Fibrin-specific poly(N-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) reestablish 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). In vitro, 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. In vivo, FSNs localize to fibrin in injured heart tissue and, when loaded with tPA and Y-27632, showed significant improvement in left ventricular ejection fraction two and four weeks post-I/R, as well as significantly decreased infarct size, -smooth muscle actin expression, and connective tissue growth factor expression four weeks post-I/R. Together, these data demonstrate the feasibility of this targeted therapeutic strategy to improve cardiac function following MI.
PMID: 30016078 [PubMed – as supplied by publisher]