Abstract 344: Incretin-Loaded Nanocarriers for Glucose Control, Therapy and Imaging of Atherosclerosis

Abstract

Background: Glucagon-like peptide-1 (GLP-1) is a key regulator of glucose control via interaction with the GLP-1 receptor (GLP-1R). GLP-1R is G-protein coupled receptor that signals through PKA-cAMP widely expressed on various cells including innate immune cells. Objective: To develop MRI-visible nanoparticles (NPs) carrying a GLP-1 mimetic Liraglutide (NP-Lira) and to test the hypothesis if NP-Lira accumulates in atherosclerosis and exerts anti-inflammatory and lipoprotein effects. Methods and Results: High-fat fed ApoE -/- mice were injected with a single dose of Lira-NP or Naked-NP followed by an oral glucose challenge. Glucose control was significantly improved with NP-Lira but not with NP-Naked ( Fig. A ). Fast protein liquid chromatography demonstrated that VLDL-apoB levels were significantly decreased by 66% at 2 hrs with NP-Lira vs. NP-controls together with reduction of triglycerides ( Fig. B, C ). Imaging of aortic plaque on a 9.4 T magnet revealed that NP-Lira accumulated in atherosclerosis as evidenced by increase in plaque CNR by 256% as compared to pre-injection ( Fig. D ). In vitro experiments demonstrated potent effects of NP-Lira vs NP-Naked in reducing pro-inflammatory gene expression and potentiation of in vitro cholesterol efflux via c-AMP dependent mechanisms. Conclusion: Nanocarriers containing GLP-1 reduce post-prandial lipids and glucose control. We postulate that their concomitant accumulation within plaque may result in favorable effects on inflammation and cholesterol efflux.