Wednesday, October 19, 2011: 1:45 PM
L100 H (Minneapolis Convention Center)
Atherogenesis 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, work by inhibiting cholesterol production; however, they do not specifically target inflamed vasculature or improve the vascular condition. Few studies have focused on antibody organization and mobility as an approach to improve drug delivery vehicle binding and uptake. Here, we present a biomimetic liposomal design targeting vascular adhesion molecule (VCAM) and endothelial leukocyte adhesion molecule (ELAM), which are upregulated on inflamed endothelial cells and localize within lipid rafts. The unique feature of this drug delivery strategy is that it allows for rearrangement of antibodies, which closely mimics in vivo antibody-receptor interactions. Temperature-induced antibody mobility is achieved by the liposome formulation; liposomes are comprised of the lipids 18:1 (Δ9-trans) 1,2-dielaidoyl-sn-glycero-3-phosphoethanolamine (DEPE) (Tm = 38°C) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-dodecanoyl (N-dod-DOPE). At temperatures below 38°C, DEPE:N-dod-DOPE liposomes are in the liquid-ordered state and the conjugated antibodies have limited mobility; above 38°C, DEPE:N-dod-DOPE liposomes enter the liquid-disordered state, and the conjugated antibodies exhibit higher lateral mobility. Thus, liposomes initially have a low binding affinity (liquid-ordered) that may be triggered by a temperature increase to have a strong binding affinity (liquid-disordered). We hypothesize that an increase in antibody mobility will allow antibodies to re-organize to complement cell surface receptors and will increase cellular uptake in inflamed areas at temperatures exceeding 38°C. Our results show that activated HUVECs incubated with 1:1 anti-VCAM:anti-ELAM immunoliposomes at 41°C exhibit a higher uptake than at 37°C. This trend was observed for both 6 hr and 24 hr activation periods. We have developed a temperature-responsive drug delivery system that enhances endothelial cellular uptake due to antibody synergy and antibody mobility. Drug delivery vehicles with triggered molecular organization may be useful for increasing circulation time and increasing uptake in sites of inflammation.