Abstract 17815: The Effects of Nanoparticle-mediated PPARγ Agonist Delivery on Plaque Stabilization: A Multichannel High-resolution Intravital Imaging Analysis

Abstract

Introduction: Plaque inflammation is associated with fibrous cap destabilization and rupture. Hypothesis: We hypothesized that the specific delivery of a novel PPARγ agonist, lobeglitazone, to inflamed plaques via nanoparticle (NP) targeting mannose receptors on macrophages could reduce inflammation in atheromata and thus, tested it using serial optical intravital molecular imaging. Methods and Results: A novel near-infrared fluorescence (NIRF) probe was fabricated by chemically conjugating thiolated glycol chitosan with mannose-PEG, and NIRF dye Cy5.5 (ext/emi 675/694 nm) for imaging. Lobeglitazone was incorporated into NIRF-NP targeting macrophage mannose receptors (MMR). In vitro, MMR-NIRF-NP was selectively uptaken by RAW264.7 cells, and NIRF signals were estimated to be 10-fold over control group (p<0.01). In ELISA and immunoblot analysis, lobeglitazone-incorporated MMR-NIRF-NP significantly decreased inflammatory cytokines. To assess the therapeutic effects in vivo, macrophage activity in the carotid plaques of apoE-/- mice were serially imaged using a customized multichannel intravital fluorescence microscope (IVFM) under mechanical carotid stabilization. After baseline imaging, lobeglitazone-loaded MMR-NIRF-NPs were intravenously injected (7 mg/kg, twice weekly) and plaque NIRF signals were compared with p.o. treated group and controls. Four weeks later, IVFM at the same plaques revealed that macrophage signals much more decreased in lobeglitazone-loaded NP treated mice compared to those at baseline, and controls (P<0.05). FM and immunostainings corroborated the in vivo findings. Conclusions: Lobeglitazone-incorporated MMR-NIRF-NP was able to selectively target and image atheroma macrophages, and effectively reduce plaque inflammation as assessed by intravital optical imaging. NP-mediated lobeglitazone delivery could be a promising therapeutic strategy for high-risk plaque stabilization.