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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-09-2853.
Submitted September 18, 2002
Accepted January 7, 2003
ICAM-directed vascular immunotargeting of anti-thrombotic agents to the endothelial luminal surface
Juan-Carlos Murciano, Silvia Muro, Lauren Koniaris, Melpo Christofidou-Solomidou, David W Harshaw, Steve M Albelda, D Neil Granger, Douglas B Cines, and Vladimir R Muzykantov*
Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, PA, USA
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
Department of Physiology, Louisiana State University, Shreveport, LA, USA
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA
* Corresponding author; email: muzykant{at}mail.med.upenn.edu.
Drug targeting to a highly expressed, non-internalizable 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 anti-thrombotic drugs to the pulmonary vascular lumen. ICAM-1 antibodies bind to the surface of endothelial cells in culture, perfused lungs and in vivo. Pro-inflammatory cytokines enhance anti-ICAM binding to the endothelium without inducing internalization. 125I-labeled anti-ICAM and a reporter enzyme ( -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, e.g., 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.
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