Abstract 15889: Nanoparticle-Mediated Selective Delivery into Lesions of Myocardial Ischemia-Reperfusion Injury Enhances Cardioprotection by Cyclosporine A in Mice
Background: Therapeutic effect of early reperfusion in acute myocardial infarction (AMI) is limited by ischemia-reperfusion (IR) injury that is known to cause cardiomyocyte necrosis through opening of mitochondrial permeability transition pore (mPTP). Cyclosporine A (CsA) is a potent inhibitor of mPTP opening, and its use at the time of reperfusion can reduce MI size in animals and small clinical study. Because the clinical use of CsA may be limited by adverse effects including renal injury and non-ischemic cardiomyocyte dysfunction, selective delivery of CsA to IR lesions would be preferable. Hence we tested the hypothesis that nanoparticle (NP)-mediated selective delivery of CsA to IR lesions enhances cardioprotective effects of CsA.
Methods and Results: In a murine model of a 30-min myocardial IR (Fig A), cellular distribution of PLGA NP containing FITC (FITC-NP) or FITC solution was examined. Significant fluorescence FITC signals were noted exclusively in cardiomyocytes of IR lesions after intravenous injection of FITC-NP at the time of reperfusion (Fig B). Interestingly, greater FITC signals were detected in subcellular mitochondrial fractions than in cytosolic fractions from the IR heart (Fig C). Intravenous treatment with CsA at a dose of 10 mg/kg, but not at 1 and 2.5 mg/kg, reduced MI size. Importantly, treatment with CsA-NP containing 1, 2.5, and 10 mg/kg CsA reduced MI size to the similar extent as seen with CsA at 10 mg/kg (Fig D). Treatment with CsA-NP at 1 mg/kg and CsA at 10 mg/kg equally inhibited leakage of cytochrome C from mitochondria, a marker of mPTP opening.
Conclusions:NP-mediated selective delivery to IR lesions, especially to mitochondria fraction of cardiomyocyte, enhanced cardioprotection by CsA. CsA-NP can be developed as a more effective and safer inhibitor of mPTP opening, compared to CsA. Targeting the opening of mPTP with CsA-NP may offer organ protection from IR injury in AMI and other clinical settings (intraoperative cardioprotection).
- © 2012 by American Heart Association, Inc.