The role of antibody synergy and membrane fluidity in the vascular targeting of immunoliposomes.

摘要

Targeted drug delivery to inflamed or injured vascular endothelial cells (ECs) and smooth muscle cells (SMCs) may provide a precise and effective therapeutic treatment for cardiovascular diseases. Upregulation of cytokine-regulated cell surface receptors, intercellular cell adhesion molecule-1 (ICAM) and endothelial-leukocyte adhesion molecule-1 (ELAM), on ECs and SMCs are used to target drug delivery vehicles. Recent studies demonstrate clustering of these molecules in lipid rafts may affect binding due to a nonhomogenous presentation of antibodies. We hypothesized that altering the antibody ratio for ICAM and ELAM (aICAM:aELAM) and mobility would influence cellular targeting. To alter antibody mobility, liposomes were prepared from either 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC, C(18:1), T(m)=-20 degrees C) or 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC, C(16:0), T(m)=42 degrees C) which are in the liquid crystalline (L(alpha)) and gel phase (L(beta)) at 37 degrees C, respectively. We report that cellular binding of DOPC immunoliposomes by ECs is maximal at an equimolar ratio of aICAM:aELAM whereas DPPC immunoliposomes showed no ratio dependence and binding was reduced by more than 2-fold. SMCs, which do not express ELAM, show a dependence on aICAM surface density. These results suggest that antibody mobility and molar ratio play a key role in increasing receptor-mediated cell targeting.