Abstract 5860: Nanoparticle-Mediated Endothelial Cell-Selective Delivery of Statin Increases Functional Collateral Vessel Development (Arteriogenesis) and Prevents Exercise-Induced Ischemia in Rabbit Hindlimb Ischemia
Recent clinical trials designed to induce therapeutic neovascularization for heart and limb ischemia by angiogenic growth factors failed to demonstrate a clinical benefit and produced some undesired side effects. Statins increase the angiogenic activity of endothelial cells and augment collateral vessel development in ischemic organs in experimental animals; however, clinical feasibility of statins’ angiogenic effects is hampered by the fact that its beneficial effects manifested only at excessively high doses. Therefore, we assessed the hypothesis that targeted delivery of statins at clinically relevant low dose to endothelial cells using nanoparticle (NP) induces therapeutic neovascularization. Seven days after induction of hindlimb ischemia in rabbits, animals were injected with PBS, FITC-loaded-NP, pitavastatin (0.5 mg/kg), or pitavastatin (0.05, 0.15, and 0.5 mg/kg)-loaded-NP (n=6, each) into ischemic muscle. FITC-NP was detected in endothelial cells of ischemic muscles for up to 4 weeks. Treatment with statin (0.5 mg/kg)-NP, but not other treatments, induced angiographically-visible arteriogenesis (Figure A⇓). Pretreatment with VEGF antagonist (PTK787) blunted these effects. In addition, statin-NP prevented exercise-induced ischemia forced by electrical stimulation (Figure B⇓), suggesting the development of functional collateral vessels. This nanotechnology platform (NP-mediated endothelial cell selective delivery of statin) may be developed as a clinically feasible and promising therapeutic strategy for severe coronary and peripheral artery diseases.