Abstract 1320: A Novel Nanotechnology-Based Strategy for Therapeutic Neovascularization: Local Delivery of Statin with Biodegradable Polymeric Nanoparticle Improves Therapeutic Efficacy of Ischemic Neovascularization
[Background] It has been shown that “systemic” administration of statins (HMG-CoA reductase inhibitor); (1) increases the number and function of endothelial progenitor cells (EPCs); (2) stimulates incorporation of EPCs to ischemic/injured tissues; and (3) accelerates regeneration/healing of damaged tissues. However, these beneficial effects have been exclusively noted at doses extremely higher than those used in the clinical settings. Therefore, “local” nanoparticle-mediated delivery should be a clinically feasible approach with minimal systemic side effects. In this study, we aimed to develop a novel local delivery system using biodegradable polymeric nanoparticle technology, and to examine whether the nanoparticle-mediated local delivery of statin at clinical dose range is useful to improve ischemic neovascularization.
[Methods and Results] To develop a novel nanotechnology-based delivery system, we prepared biodegradable poly-lactide-glycolide copolymer nanoparticles (NPs) with a mean diameter of 200 nm by the emulsion solvent diffusion method. We then produced unilateral hindlimb ischemia in mice, which were injected with FITC-loaded NPs (0.16 mg/100 βl), or atorvastatin [0.01 mg/100 μl (0.5 mg/kg)], or statin-loaded NPs (0.16 mg/100 μl, containing 0.01 mg of atorvastatin) into ischemic muscles immediately after induction of hindlimb ischemia (n=8 to 12 each). Trace experiments showed that FITC was uptaken by almost all cells in the injected ischemic sites. Laser Doppler and morphometric analyses showed that single injection of statin-loaded NPs, but not FITC-loaded NPs or atorvastatin, significantly enhanced recovery of blood perfusion to the ischemic limb, increased capillary and artery density, and reduced skeletal muscle necrosis /degeneration. Neither group of mice showed the signs of rhabdomyolysis, such as an elevation of myoglobin.
[Conclusion] We have shown the successful intracellular delivery of statin in ischemic tissues using our nanoparticle technology, and therapeutic effects on ischemia-induced neovascularization in mice with no potential side effects. The present data demonstrates the potential therapeutic benefits of our nanotechnology-based strategy for therapeutic neovascularization.