ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface.

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TitleICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface.
Publication TypeJournal Article
Year of Publication2003
AuthorsMurciano, J-C, Muro, S, Koniaris, L, Christofidou-Solomidou, M, Harshaw, DW, Albelda, SM, D Granger, N, Cines, DB, Muzykantov, VR
Date Published2003 May 15
KeywordsAnalysis of Variance, Animals, Antibodies, Biological Transport, Cell Membrane, Endothelium, Vascular, Fibrinolytic Agents, Intercellular Adhesion Molecule-1, Liver, Lung, Male, Rats, Rats, Sprague-Dawley, Spleen, Tissue Distribution, Tissue Plasminogen Activator

Drug targeting to a highly expressed, noninternalizable determinant up-regulated on the perturbed endothelium may help to manage inflammation and thrombosis. We tested whether inter-cellular adhesion molecule-1 (ICAM-1) targeting is suitable to deliver antithrombotic drugs to the pulmonary vascular lumen. ICAM-1 antibodies bind to the surface of endothelial cells in culture, in perfused lungs, and in vivo. Proinflammatory cytokines enhance anti-ICAM binding to the endothelium without inducing internalization. (125)I-labeled anti-ICAM and a reporter enzyme (beta-Gal) conjugated to anti-ICAM bind to endothelium and accumulate in the lungs after intravenous administration in rats and mice. Anti-ICAM is seen to localize predominantly on the luminal surface of the pulmonary endothelium by electron microscopy. We studied the pharmacological effect of ICAM-directed targeting of tissue-type plasminogen activator (tPA). Anti-ICAM/tPA, but not control IgG/tPA, conjugate accumulates in the rat lungs, where it exerts plasminogen activator activity and dissolves fibrin microemboli. Therefore, ICAM may serve as a target for drug delivery to endothelium, for example, for pulmonary thromboprophylaxis. Enhanced drug delivery to sites of inflammation and the potential anti-inflammatory effect of blocking ICAM-1 may enhance the benefit of this targeting strategy.

Alternate JournalBlood
PubMed ID12531816
Grant ListHL 60290 / HL / NHLBI NIH HHS / United States
HL60169 / HL / NHLBI NIH HHS / United States
R01 HL/GM 71175-01 / HL / NHLBI NIH HHS / United States
R03 TW01468 / TW / FIC NIH HHS / United States