Abstract 225: Anti-atherosclerotic Effects of Plaque Macrophage Targetable Nanoparticle-mediated PPAR-γ Agonist Delivery in Atherogenic Mice

Abstract

Introduction: Atherosclerosis is a process of lipid accumulation and inflammation. In particular, plaque macrophages are associated with fibrous cap destabilization and rupture. We hypothesized that the specific delivery of a PPAR-γ agonist to inflamed plaques via nanoprobe (NP) targeting macrophage mannose receptors could reduce plaque burden and inflammation. Methods and Results: Macrophage mannose receptor targetable nanoprobe (MMR-NP) was fabricated by chemically conjugating thiolated glycol chitosan with mannose-PEG-maleimide, followed by incorporating PPAR-γ agonist (lobeglitazone) into this nanoscale delivery system (MMR-Lobe). For in vivo monitoring of therapeutic response, near-infrared fluorescence NP was prepared by conjugation of Cy5.5 (ext/emi 675/694 nm) with MMR-NP. In cellular uptake study, the MMR-NP showed high affinity to mannose receptors on macrophages. MMR-Lobe attenuated LPS-induced inflammatory cytokines such as TNF-α, IL-6, and MMP-9 in RAW264.7 cells. Additionally, MMR-Lobe increased expression of ABCA1, ABCG1 and LXR-α, known as PPAR-γ regulator genes involved in cholesterol efflux, in RAW264.7 cells. Using a customized high-resolution intravital fluorescence microscope, the in vivo serial imaging of carotid atheroma in apoE-/- mice injected with MMR-Lobe (7 mg/kg, twice weekly for 4 weeks) revealed a significant decrease in plaque burden and inflammation (Figure) as compared to baseline, or non-treated controls, or p.o. Lobe treated mice (p<0.01 respectively, 6 mice in each group). En face imaging, FM, and immunostainings corroborated the in vivo findings. Conclusions: MMR-Lobe was able to selectively target atheroma macrophages, and effectively reduce both plaque burden and inflammation as assessed by serial intravital optical imaging. We suggest that nanoprobe-mediated PPAR-γ agonist delivery targeting plaque macrophages holds a promising theranostic approach for high-risk atheromata.