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Prepublished online as a Blood First Edition Paper on January 16, 2003; DOI 10.1182/blood-2002-09-2853.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 3977-3984
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
ICAM-directed vascular immunotargeting of antithrombotic
agents to the endothelial luminal surface
Juan-Carlos Murciano,
Silvia Muro,
Lauren Koniaris,
Melpo Christofidou-Solomidou,
David W. Harshaw,
Steven M. Albelda,
D. Neil Granger,
Douglas B. Cines, and
Vladimir R. Muzykantov
From the Institute of Environmental Medicine,
Department of Pharmacology, Department of Medicine, Department of
Pathology and Laboratory Medicine, University of Pennsylvania,
Philadelphia, PA; and the Department of Physiology, Louisiana State
University, Shreveport, LA.
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. 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, 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.
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