Investigating the effect of liposomal membrane fluidity and antibody lateral mobility on endothelial cell targeting

Atherosclerosis is initiated by the adhesion of leukocytes to the endothelial surface of arteries followed by migration beneath the intima. Current therapies to combat atherosclerotic plaque, such as statins or antihypertensive drugs, treat atherosclerosis indirectly; they do not specifically target inflamed vasculature or improve the vascular condition. Few studies have focused on antibody mobility or membrane fluidity as an approach to improve drug delivery vehicle binding and uptake.;Here, we present a biomimetic liposomal design targeting vascular adhesion molecule (VCAM1) and E-selectin, which are upregulated on inflamed endothelial cells (ECs). We hypothesized that increased lateral antibody diffusivity may be used as a strategy to enhance liposome targeting to ECs expressing high levels of VCAM1 and E-selectin. We first characterized the physical properties of our liposomal system, including membrane fluidity and quantification of antibody surface density, and evaluated the temporal EC expression of VCAM1 and E-selectin. We then examined the effects of membrane fluidity, antibody surface density, and incubation time on activated EC binding and uptake. Finally, we also conducted a preliminary in vivo study where we assessed the biodistribution of our liposomes.;The results of this dissertation may be utilized to design liposomes with enhanced targeting efficiency to inflamed endothelium, present not only in atherosclerosis but also in a wide range of vascular inflammatory conditions. These liposomes can be further developed to have diagnostic, imaging and/or therapeutic capabilities.