Abstract 495: Effect Of Lipid Composition On The Atheroprotective Properties Of High-Density Lipoprotein-Mimicking Micelles

Abstract

An imbalance of cholesterol metabolism and unresolved local inflammation on the arterial wall drives atherosclerosis progression. Synthetic high-density lipoproteins (sHDL) have been shown to promote reverse cholesterol transport and reduce vascular inflammation, but producing sHDL at a large scale is challenging due to the difficulty in manufacturing recombinant Apolipoprotein A-I. HDL-mimicking micelles have been designed to mimic the structure and function of HDL. Prior research has shown that the phospholipid (PL) composition of HDL affects its overall activity, thus we have examined how PL composition of micelles affects it’s anti-inflammatory properties and cholesterol mobilization capacity. Micelles were composed four phosphatylcolines (PC), either POPC, DMPC, DPPC or DSPC, and DSPE-PEG2k. A second library of micelles was created using different ratios of DMPC and DSPE-PEG. Micelles ranged from 14 to 28 nm in diameter in size. In vitro , POPC and DMPC micelles were able to reduce TNF-α and IL-6 cytokine levels, diminish activation of nuclear factor-κB (NF-κB) and dissolve cholesterol crystals to a greater extent than DPPC and DSPC micelles. 1:2 DMPC:DSPE-PEG micelles caused the greatest percentage of cholesterol effuxed from cells (~8%) . In vivo PK/PD results showed that the PC composition does not greatly affect the PK or cholesterol mobilization of micelles. On the contrary, micelles with a 1:3 DMPC:DSPE-PEG ratio had a larger AUC (22815.2 mg*h/dL) and C max (775.0 mg/dL) when compared to the 1:0.5 ratio micelles (14266.1 mg*h/dL and 523.2 mg/dL, respectively). The maximum amount of cholesterol mobilized over 48 hours was also greater in the 1:3 ratio vs 1:0.5 ratio micelles (7813.3 mg*h/dL vs 3883.3 mg*h/dL). In conclusion, the composition of HDL-mimicking micelles affects it’s in vitro anti-atherosclerotic properties, such as reduction of pro-inflammatory cytokine release, diminished activation of NF-kB, cholesterol crystal dissolution and cholesterol efflux capabilities, as well as cholesterol mobilization in vivo . Further investigation must be completed in order to fully understand how lipid properties influence the therapeutic potential of micelles to treat atherosclerosis.