Abstract 5798: Nanoparticle-mediated Endothelial Cell-selective Delivery of Pioglitazone Improves Therapeutic Efficacy of Ischemic Neovascularization
Background: Recent studies suggest that a peroxisome proliferator activated receptor-γ (PPARγ) agonist pioglitazone reduces the incidence of ischemic cardiovascular events. However, it is unknown if pioglitazone induces therapeutic neovascularization after induction of ischemia. Moreover, novel drug delivery system may alleviate potential adverse effects of systemic administration of PPARγ agonists. We recently reported that intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into vascular endothelial cells of ischemic muscles for 2 weeks post-injection in a murine model of hindlimb ischemia. Hence, we tested the hypothesis that nanoparticle (NP)-mediated endothelial cell selective delivery of pioglitazone is an effective therapy to induce ischemic neovascularization in vivo.
Methods and Results: In a murine model of hindlimb ischemia, systemic oral administration of pioglitazone at a dose of 1000 μg/kg per day, but not other lower doses, enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis 3 weeks after induction of ischemia (Figure A⇓). In contrast, single intramuscular injection of NP incorporated with pioglitazone at 1 or 10 μg/kg into ischemic muscles immediately after induction of ischemia significantly enhanced ischemic neovascularization at 3 weeks post-ischemia (Figure B⇓). Intramuscular injection of PBS, FITC-NP, or pioglitazone only at 1–10 μg/kg showed no effects on blood perfusion to the ischemic limb.
Conclusion: NP-mediated endothelial cell-selective delivery of pioglitazone may effectively induce therapeutic neovascularization.