Atherosclerosis is the main cause of death due to coronary heart disease (CHD). Foam cells formed from excess cholesterol accumulation into macrophages result in atherosclerotic plaques [1]. Reverse cholesterol transport (RCT) is one of the strategies to combat atherosclerosis, in which high-density lipoprotein (HDL) transport cholesterol from peripheral tissues to the liver for biliary excretion [2]. HDL is nature’s own dynamic nanoparticle (NP) for cholesterol uptake and reverse transport. Natural HDLs have been utilized as therapeutic vehicles for drugs and imaging agents. Currently, most of the studies are focused on the reconstituted HDL (rHDL) containing human apolipoprotein AI (ApoAI), nanocrystal HDL, and inorganic nanocrystals to replace the natural HDL core. However, rHDL NPs have potential problems, such as batch-to-batch variability, scale-up challenges, and safety issues. Our lab recently developed a mitochondria targeted completely synthetic HDL/apoA-I mimicking NP composed of biodegradable polymer, lipid, and a ApoAI mimetic L-4F peptide [3]. Cardiolipin is a phospholipid which is present in the inner mitochondrial membrane [4]. It plays an important role during the formation of contact sites between the inner and outer mitochondrial membranes. We hypothesized that a completely synthetic mitochondria targeted HDL/apoA-I mimicking NP containing cardiolipin as lipid component will participate in the intracellular cholesterol transport process to remove the excess cholesterol. In this presentation, construction, optimization, and mechanism of action of this new generation of mitochondria targeted cardiolipin containing HDL mimicking NPs and comparison of its activity with the first generation of HDL-NPs [3] will be discussed. 1. Luthi, A.J., et al., Tailoring of Biomimetic High-Density Lipoprotein Nanostructures Changes Cholesterol Binding and Efflux. ACS Nano, 2011. 6(1): 276-285. 2. Luthi, A.J., et al., Nanotechnology for synthetic high-density lipoproteins. Trends in molecular medicine, 2010. 16(12): 553-560. 3. Marrache, S. and S. Dhar, Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis. Proceedings of the National Academy of Sciences, 2013. 110(23): 9445-9450. 4. Houtkooper, R. and F. Vaz, Cardiolipin, the heart of mitochondrial metabolism. Cellular and Molecular Life Sciences, 2008. 65(16): 2493-2506.

Mitochondria targeted cardiolipin based high density lipoprotein mimicking nanoparticles for  atherosclerosis

249th National Meeting (2015)

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