IMMUNOTARGETING OF LIPOSOMES TO ACTIVATED VASCULAR ENDOTHELIAL-CELLS - A STRATEGY FOR SITE-SELECTIVE DELIVERY IN THE CARDIOVASCULAR-SYSTEM

Endothelial-selective delivery of therapeutic agents, such as drugs or genes, would provide a useful tool for modifying vascular function in various disease states, A potential molecular target for such deliver y is E-selectin, an endothelial-specific cell surface molecule express ed at sites of activation ill vivo and inducible in cultured human umb ilical vein endothelial cells (HUVEC) by treatment with cytokines such as recombinant human interleukin 1 beta (IL-1 beta). Liposomes of var ious types (classical, sterically stabilized, cationic, pa-sensitive), each conjugated with mAb H18/7, a murine monoclonal antibody that rec ognizes the extracellular domain of E-selectin, bound selectively and specifically to IL-1 beta-activated HUVEC at levels up to 275-fold hig her than to unactivated HUVEC. E-selectin-targeted immunoliposomes app eared in acidic, perinuclear vesicles 2-4 hr after binding to the cell surface, consistent with internalization via the endosome/lysosome pa thway, Activated HUVEC incubated with E-selectin-targeted immunoliposo mes, loaded with the cytotoxic agent doxorubicin, exhibited significan tly decreased cell survival, whereas unactivated HUVEC were unaffected by such treatment, These results demonstrate the feasibility of explo iting cell surface activation markers for the endothelial-selective de livery of biologically active agents via immunoliposomes. Application of this targeting approach in vivo may lead to novel therapeutic strat egies in the treatment of cardiovascular disease.