Abstract 14130: Nanoparticle-mediated Endothelial Cell-selective Delivery of Pioglitazone Enhances Therapeutic Efficacy of Therapeutic Angiogenesis and Arteriogenesis after Hindlimb Ischemia in Mice
Background: Recent studies suggest that a peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO) improves endothelial function and reduces the incidence of ischemic cardiovascular events. However, it is unknown if PIO directly induces therapeutic neovascularization after ischemia. Moreover, novel drug delivery system may alleviate potential adverse effects of systemic administration of PPARγ agonists. We recently created NP-mediated endothelial cell-selective delivery system with the use of bioabsorbable polymeric nanoparticles (NP) in order to develop the more effective and safer strategy of therapeutic neovascularization.
Hypothesis: We tested the hypothesis that NP-mediated endothelial cell selective delivery of PIO enhances therapeutic efficacy of therapeutic neovascularization.
Methods and Results: In a murine model of hindlimb ischemia, single intramuscular injection of PIO-incorporated NP (PIO-NP) at 1 and 10 μg/kg into ischemic muscles immediately after induction of ischemia improved blood flow recovery in the ischemic limbs (Figure A, 48±6 vs. 71±12 % for FITC-NP and PIO-NP group, P<0.05), and increased arteriolar density (5.7±0.8 vs. 12±0.9 /mm2, P<0.001) at 3 weeks post-ischemia. By contrast, intramuscular injection of PBS, FITC-NP, or PIO alone at same dose had no therapeutic effects. Oral daily administration of PIO at 1000 μg/kg per day for 3 weeks did show significant therapeutic effects (Figure B). The beneficial effects of PIO-NP were reversed in mice administered GW9662, a PPAR-γ antagonist (Figure C).
Conclusions: This mode of NP-mediated endothelial cell-selective delivery of PIO at 1 μg/kg is extremely more effective in inducing therapeutic angiogenesis and arteriogenesis compared with the systemic administration of PIO (total dose: 21000 μg/kg) in this model. This nanotechnology platform may represent a significant advance in therapeutic neovascularization over current approaches.
- © 2010 by American Heart Association, Inc.