Abstract 15162: Nanoparticle-Mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-Reperfusion Injury

Abstract

Backcround: Targeting one mediator of myocardial ischemia-reperfusion (IR) injury failed to successfully reducing infarct size in clinical trials; therefore, an innovative approach may be to target more than 2 mediators at a time. Previously, we have engineered poly(lactic acid/glycolic acid) nanoparticle containing cyclosporine A (CsA-NP) and pitavastatin (Pitava-NP), and reported that the former inhibits the opening of mitochondrial permeability transition pore (mPTP) and the latter reduces monocyte-mediated inflammation in IR hearts. Here we tested the hypothesis that nanoparticle-mediated simultaneous targeting to mitochondria and monocytes confers additive and ultimate cardioprotection against IR injury. Methods and Result: In a murine model of myocardial IR injury, simultaneous treatment with CsA-NP and Pitava-NP at the time of reperfusion showed additive reduction in IR injury (infarct size) in wild-type mice (Fig. A). In cyclophilin D (CypD, a key regulatory molecule for mPTP opening)-KO mice, Pitava-NP reduced IR injury and recruitment of Ly6Chigh inflammatory monocytes whereas CsA-NP had no therapeutic effcts (Fig. B). In contrast, CsA-NP reduced IR injury in CCR2 (a receptor for monocyte chemoattractant protein-1)-KO mice. Flow cytometric analysis revealed that Pitava-NP, but not CsA-NP, inhibited the recruitment of Ly6Chigh inflammatory monocytes into IR heart. We then produced CypD/CCR2 -knockout mice and found that the double-KO mice displayed dramatic reduction in IR injury (Fig. C). Fluorescence molecular tomography showed that inflammation was markedly inhibited in CCR2-KO and CypD/CCR2-KO mice while residual inflammation was noted in CypD-KO mice (Fig. D). Conclusions: Nanoparticle-mediated simultaneous targeting to mitochondria and inflammatory monocytes can be developed as a novel therapeutic strategy that offers ultimately adequate cardioprotection in acute myocardial infarction and other clinical settings.