Abstract 3605: Nanoparticle-based Monocyte-Selective Delivery of PPARγ Agonist Pioglitazone Inhibits Plaque Rupture in ApoE-Deficient Mice
Background: Preventing plaque rupture is the most effective strategy to reduce acute coronary syndrome (ACS). Monocytes/macrophages play a key role in plaque destabilization and rupture leading to ACS. Recent studies suggest that a peroxisome proliferator activated receptor-γ (PPARγ) agonist pioglitazone may reduce ACS, however, it is unknown (1) whether pioglitazone substantially reduces plaque ruptures and (2) whether pioglitazone acts through monocytes. Hence, we assessed our hypothesis that nanoparticle (NP)-based monocyte-selective delivery of pioglitazone prevents plaque rupture.
Method and Results: We engineered bioabsorbable PLGA nanoparticles (mean diameter = 200 nm) containing pioglitazone (Pio-NP) or FITC (FITC-NP). Flow cytometry and histology revealed that FITC-NP was selectively delivered to CD11b+ peripheral monocytes after intravenous administration to ApoE-deficient mice. We evaluated number of buried fibrous caps as plaque ruptures in the brachiocephalic arteries in a mouse model of plaque rupture (Figure, A⇓). Weekly intravenous treatment with Pio-NP, but not FITC-NP or oral administration of pioglitazone, significantly inhibited plaque ruptures (Figure, B, C⇓). Pio-NP stabilized plaque phenotype through increase in fibrous cap thickness (FITC-NP 1.6±0.3 vs Pio-NP 3.6±0.8 μm, p<0.05). Quantitative PCR analysis revealed that Pio-NP significantly downregulated MCP-1, RANTES, EMMPRIN and MMP-13 in abdominal macrophages.
Conclusion: NP-based monocyte-selective delivery of pioglitazone at a clinically relevant low dose alters macrophage into less inflammatory phenotype and prevents plaque destabilization and ruptures.