Inhibition of Apoptosis Through Localized Delivery of Rapamycin-Loaded Nanoparticles Prevented Neointimal Hyperplasia and Reendothelialized Injured Artery

Background-A significant fraction of vascular smooth muscle cells (VSMCs) undergo rapid apoptosis after balloon angioplasty. In this study, we tested the hypothesis that protecting VSMCs from undergoing apoptosis prevents the cascade of events that lead to intimal hyperplasia. Methods and Results-Rapamycin-loaded gel-like nanoparticles (mean diameter, 54 +/- 5 nm) were infused locally in a rat carotid artery model of vascular injury. The drug has both antiapoptotic and antiproliferative effects on VSMCs and hence was selected for the current study. Localized delivery of nanoparticles sustained the drug level in the target artery for > 2 weeks; demonstrated significant inhibition of hyperplasia (intima/media ratio, 1.5 +/- 0.02 versus 2.7 +/- 0.6; P < 0.01); and most importantly, reendothelialized the injured artery (endothelium coverage: treated 82% versus control 28%). We also demonstrated inhibition of activation of caspase-3/7 enzymes in the treated artery, preventing VSMCs from undergoing apoptosis and subsequent infiltration of macrophages. Conclusions-It may be postulated that the localized delivery of rapamycin inhibited apoptosis of VSMCs, minimizing the inflammatory response to the injury and, thus, creating conditions conducive to vascular repair (reendothelialization). Unlike stenting, which can lead to thrombosis and increased risk for in-stent restenosis, our approach could eliminate or minimize long-term complications because the injured artery undergoes a natural process of reendothelialization. (Circ Cardiovasc Intervent. 2008;1:209-216.)