Bioinspired Drug Delivery: Cooperative Adhesion via Tunable Antibody Organization

Atherogenesis is initiated by leukocyte adhesion to the endothelium followed by an enhanced inflammatory response. Current therapies combating atherosclerosis do not specifically target inflamed vasculature. Here, we present a biomimetic liposomal design targeting vascular adhesion molecule-1 (VCAM-1) and E-selectin, which are upregulated on inflamed endothelial cells (ECs). The unique feature of this drug delivery strategy is that it allows for rearrangement of antibodies and thus closely mimics in vivo antibody-receptor interactions. Tunability of antibody mobility can be achieved by the liposome formulation; liposomes are comprised of lipids with varying degrees of membrane fluidity. Antibodies conjugated to liposomes characterized with low membrane fluidity have limited mobility; while antibodies conjugated to highly fluid liposomes exhibit higher lateral mobility. We hypothesize that an increase in antibody mobility will allow antibodies to re-organize to complement cell surface receptors and will thus increase cellular uptake in inflamed areas. Mixtures of aVCAM-1:aE-selectin antibodies were conjugated to liposomes encapsulating rhodamine-conjugated dextran via carbodiimide chemistry. ECs activated with interleukin-1α represented an in vitro model of EC inflammation. ECs were incubated with immunoliposomes having varying membrane fluidity and conjugated with different ratios of aVCAM-1:aE-selectin. Liposome uptake by ECs was analyzed using flow cytometry. Our results show that activated ECs incubated with 1:1 aVCAM-1:aE-selectin immunoliposomes having higher membrane fluidity exhibit a higher uptake than ECs incubated with less fluid immunoliposomes. We have developed a drug delivery system with tunable antibody organization that enhances endothelial cellular uptake due to its dual antibody presentation and its higher antibody mobility.