Nanoparticles-Mediated Targeting of Pioglitazone Reduces Myocardial Ischemia-Reperfusion Injury and Cardiac Remodeling by Antagonizing Monocyte/Macrophage-mediated Inflammation in Preclinical Animal Models

Abstract

Background: Monocyte-mediated inflammation is a major mechanism of myocardial ischemia-reperfusion (IR) injury and cardiac remodeling. However, no decisive anti-inflammatory therapy has been developed for clinical setting. Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, has unique anti-inflammatory effects on monocyte/macrophage. Here we tested the hypothesis that nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and inflammatory monocytes ameliorates IR injury and cardiac remodeling in preclinical animal models. Methods and Results: We formulated poly(lactic acid/glycolic acid) nanoparticle containing pioglitazone (Pio-NPs). In mouse IR model, nanoparticles were delivered predominantly to circulating monocytes and to cardiomyocytes and macrophages in the IR heart. Intravenous treatment with Pio-NPs at the time of reperfusion reduced IR injury, which was canceled by the pretreatment with PPARγ antagonist GW9662. In contrast, pioglitazone solution showed no therapeutic effects. Pio-NPs reduced inflammatory gene expression and inhibited the recruitment of Ly6Chigh inflammatory monocytes into IR heart. In mouse MI model, intravenous treatment with Pio-NPs for 3 days after LAD ligation reduced recruitment of macrophage and polarized macrophages toward an anti-inflammatory M2 phenotype, which, leads to improvement of cardiac remodeling and mortality. Finally, in a conscious mini-pig model of myocardial IR injury, Pio-NPs induced cardioprotection from IR injury, indicating the pre-clinical proof of concept. Conclusion: Nanoparticle-mediated targeting of pioglitazone can be developed as a novel modality by antagonizing monocyte-mediated inflammation in myocardial infarction. Background: Monocyte-mediated inflammation is a major mechanism of myocardial ischemia-reperfusion (IR) injury and cardiac remodeling. However, no decisive anti-inflammatory therapy has been developed for clinical setting. Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)γ agonist, has unique anti-inflammatory effects on monocyte/macrophage. Here we tested the hypothesis that nanoparticle-mediated targeting of pioglitazone into cardiomyocytes and inflammatory monocytes ameliorates IR injury and cardiac remodeling in preclinical animal models. Methods and Results: We formulated poly(lactic acid/glycolic acid) nanoparticle containing pioglitazone (Pio-NPs). In mouse IR model, nanoparticles were delivered predominantly to circulating monocytes and to cardiomyocytes and macrophages in the IR heart. Intravenous treatment with Pio-NPs at the time of reperfusion reduced IR injury, which was canceled by the pretreatment with PPARγ antagonist GW9662. In contrast, pioglitazone solution showed no therapeutic effects. Pio-NPs reduced inflammatory gene expression and inhibited the recruitment of Ly6Chigh inflammatory monocytes into IR heart. In mouse MI model, intravenous treatment with Pio-NPs for 3 days after LAD ligation reduced recruitment of macrophage and polarized macrophages toward an anti-inflammatory M2 phenotype, which, leads to improvement of cardiac remodeling and mortality. Finally, in a conscious mini-pig model of myocardial IR injury, Pio-NPs induced cardioprotection from IR injury, indicating the pre-clinical proof of concept. Conclusion: Nanoparticle-mediated targeting of pioglitazone can be developed as a novel modality by antagonizing monocyte-mediated inflammation in myocardial infarction.