Abstract 330: Targeted Nanotherapy for the Treatment of Atherosclerosis

Abstract

Objective: Atherosclerosis is the leading cause of death and disability in the United States. We hypothesize that systemic administration of a novel nanofiber will target areas of atherosclerosis and regress atherosclerotic lesions. Methods: Self assembling peptide amphiphile (PA) nanofibers were synthesized. An 18 amino acid sequence which retains the cholesterol efflux actions of apolipoprotein-A1 (apoA1) along with a Liver X Receptor (LXR) agonist, known to enhance cholesterol efflux, were incorporated into the nanofiber to both target and treat atherosclerosis. To assess the ability of the nanofiber to target and treat atherosclerosis in vivo , LDL receptor knockout mouse (LDLR KO) mice were fed a high fat diet (HFD) for 14 weeks after which they received bi-weekly injections of the therapeutic or control for 8 weeks. Optimum dose, concentration, binding duration, and biodistribution was determined using fluorescent microscopy and pixel quantification. Treatment groups included: PBS control, PA nanofiber with a scrambled targeting sequence, LXR agonist alone, targeted PA nanofiber (ApoA PA), and targeted PA nanofiber incorporating LXR agonist (ApoA-LXR PA). n=10/treatment group. Results: ApoA PA and ApoA-LXR PA nanofibers effectively targeted atherosclerotic plaque in the aortic root. Optimum concentration of nanofiber was 2mg/mL, and optimum dose was 6mg/kg. There was no difference in optimum dosing or concentration between males and female mice. ApoA PA nanofiber localized to the aortic root for approximately 2-3 days, and was cleared from the aortic root by 7-10 days. Concentrations of ApoA PA in the aortic root was 5-fold higher than in the lung, liver, and kidney one day post injection. After only 8 weeks of treatment, male and female mice treated with ApoA-LXR PA had 11 and 9% plaque area reduction compared to PBS treated controls, respectively. Differences in treatment conditions vs. controls showed sex dependence, with only male mice demonstrating significantly higher plaque reduction from ApoA1-LXR PA treatment in comparison to scrambled PA treatment. Conclusions: Our results demonstrate that a novel targeted nanofiber binds specifically to atherosclerotic lesions and reduce plaque burden after a short treatment duration.