In vitro cellular handling and in vivo targeting of E-selectin-directed immunoconjugates and immunoliposomes used for drug delivery to inflamed endothelium

Purpose. Drug targeting to activated endothelial cells is now being explored as a new approach to interfere with chronic inflammation. This study compares a dexamethasone-anti-E-selectin immunoconjugate (dexa-Ab(Esel)) with anti-E-selectin immunoliposomes (Ab(Esel)-immunoliposomes) that contain dexamethasone, regarding in vitro binding and internalization as well as in vivo accumulation in activated endothelial cells. Methods. In vitro binding and internalization of dexa-Ab(Esel) and the Ab(Esel)-immunoliposomes into TNFalpha-activated HUVECs was studied using confocal laser scanning microscopy and radiolabeled compounds. Tissue accumulation of both compounds was studied in a murine delayed-type hypersensitivity model using immunohistochemistry. Results and Conclusions. Both preparations were selectively internalized by activated endothelial cells. Dexa-Ab(Esel) was internalized by activated HUVECs to a larger extent than the Ab(Esel) immunoliposomes, although in theory the high drug-loading capacity of the liposomes may enable a larger amount of dexamethasone to be delivered intracellularly. Both dexa-Ab(Esel) and Ab(Esel) immunoliposomes accumulated in activated endothelial cells in murine inflamed skin. Ab(Esel)-immunoliposomes, but not dexa-Ab(Esel), were additionally detected in control skin, though to a lesser extent, and in macrophages of the liver and the spleen. Studies on therapeutic effects and side effects in models of chronic inflammation are now necessary to establish pharmacodynamics of dexa-Ab(Esel) and/or Ab(Esel)-immunoliposomes in the treatment of chronic inflammation.