Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE −/− Mice

Abstract

Objective— Inflammatory monocytes/macrophages produce various proteinases, including matrix metalloproteinases, and degradation of the extracellular matrix by these activated proteinases weakens the mechanical strength of atherosclerotic plaques, which results in a rupture of the plaque. Peroxisome proliferator–activated receptor-γ induces a polarity shift of monocytes/macrophages toward less inflammatory phenotypes and has the potential to prevent atherosclerotic plaque ruptures. Therefore, we hypothesized that nanoparticle-mediated targeted delivery of the peroxisome proliferator–activated receptor-γ agonist pioglitazone into circulating monocytes could effectively inhibit plaque ruptures in a mouse model. Approach and Results— We prepared bioabsorbable poly(lactic- co -glycolic-acid) nanoparticles containing pioglitazone (pioglitazone-NPs). Intravenously administered poly(lactic- co -glycolic-acid) nanoparticles incorporated with fluorescein isothiocyanate were found in circulating monocytes and aortic macrophages by flow cytometric analysis. Weekly intravenous administration of pioglitazone-NPs (7 mg/kg per week) for 4 weeks decreased buried fibrous caps, a surrogate marker of plaque rupture, in the brachiocephalic arteries of ApoE −/− mice fed a high-fat diet and infused with angiotensin II. In contrast, administration of control-NPs or an equivalent dose of oral pioglitazone treatment produced no effects. Pioglitazone-NPs inhibited the activity of matrix metalloproteinases and cathepsins in the brachiocephalic arteries. Pioglitazone-NPs regulated inflammatory cytokine expression and also suppressed the expression of extracellular matrix metalloproteinase inducer in bone marrow–derived macrophages. Conclusions— Nanoparticle-mediated delivery of pioglitazone inhibited macrophage activation and atherosclerotic plaque ruptures in hyperlipidemic ApoE −/− mice. These results demonstrate a promising strategy with a favorable safety profile to prevent atherosclerotic plaque ruptures.