Abstract 15677: Nanoparticle-Mediated Targeting of Pitavastatin Into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Pig Model

Background: There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction, for which interventional reperfusion therapy is hampered by ischemia-reperfusion (IR) injury. We recently reported that nanoparticle-mediated targeting of pitavastatin to IR myocardium exerts cardioprotection from IR injury through activation of PI3K-Akt pathway and inhibition of inflammation in rats. However, the cardioprotective effects of the poly(lactic acid/glycolic acid) nanoparticle incorporating pitavastatin (pitavastatin-NP) in large animals and its feasibility in clinical settings are unknown. To obtain a preclinical proof of concept, this study examined effects of pitavastatin-NP on IR injury in a conscious pig model. Methods and Results: Forty-eight mini-pigs (age: 4-6 months, BW: 10-15 kg) were surgically instrumented with a cuff occluder at the left circumflex coronary artery (LCX) and telemetry transmitters to continuously measure an electrocardiogram at left precordial lead, arterial blood pressure, heart rate, and body temperature. Next day when animals recovered from surgery, LCX was occluded for 60 minutes and then reperfused for 24 hours under conscious conditions (Fig. 1). Intravenous treatment with pitavastatin-NP at doses ≥ 8 mg/body 5 min before reperfusion reduced MI size (Fig. 2); by contrast, pitavastatin alone (8 mg/body) or FITC-NP showed no therapeutic effects. Treatment with pitavastatin-NP exerted no effects on arterial blood pressure heart rate, and serum blood parameters (renal and liver function)(Table), but attenuated the development of abnormal Q wave (Fig. 2). Conclusion: Nanoparticle-mediated targeting of pitavastatin protects the heart form IR injury without apparent adverse side effects in a preclinical conscious pig model. After subsequent toxicology study, we are planning to submit this result to the Investigational New Drug and carry out a phase II clinical trial.