1 research outputs found
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
polyÂ(<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