Cardiotropic ligand-guided liposomes for myocardial delivery of atorvastatin in a mouse model of myocardial infarction.

The next major advancement in managing myocardial infarction (MI) patients is to protect myocardium against ischemia-reperfusion injury. Although several cardioprotective agents are being developed, their myocardial delivery is still a challenge. In this study, we designed a novel liposome-based nanocarrier for active targeting of damaged myocardium and demonstrated delivery of atorvastatin (ATV) as a model drug. ATV-loaded liposomes were made by either extrusion or high-pressure homogenization of distearoyl phosphatidylcholine and cholesterol mixture. These liposomes were then modified with a cardiac myosin-binding ureoid amphiphilic cardiotropic ligand (CTL) to target infarcted heart tissue. CTL was synthesized as a conjugate of 1-(2-fluoro-3-(piperazin-1-yl methyl) phenyl)-3-(6-methylpyridin-3-yl) urea and PEG-distearoylphosphatidylethanolamine. The resultant liposomes were labeled with Tc for imaging and biodistribution. Myocardial injury in CD1 mice was induced either by ligating the left anterior descending artery or by treatment with high dose of isoproterenol. Tissue ATV concentration was estimated by liquid chromatography-mass spectrometer detection. Imaging and biodistribution studies showed that CTL-modified liposomes preferentially accumulated in infarcted hearts compared to normal hearts, with over five times more accumulation in MI-affected myocardium than in control hearts. Fluorescence micrographs of heart sections from mice injected with Texas Red doped CTL-liposomes supported the imaging and biodistribution data. We found that liposomes modified with 1 % CTL (M ratio) accumulated in the myocardium the most. ATV-loaded CTL-liposomes also accumulated in the heart of isoproterenol-treated mice while sparing the hearts of normal mice (12.6 ng/g vs. 1.1 ng/g, p < 0.05); plain liposomes only delivered 1.13 ng ATV per g heart tissue. In conclusion, CTL-modified liposomes effectively targeted and delivered ATV to infarcted heart tissue, promising efficient delivery of cardioprotective drugs to address ischemia-reperfusion injury and improve recovery in MI patients undergoing recanalization.