title: ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface.
abstract: 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.
authors.affiliation: Institute of Environmental Medicine, Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Murciano
authors.forename: Silvia
authors.initials: S
authors.lastname: Muro
authors.forename: Lauren
authors.initials: L
authors.lastname: Koniaris
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.forename: David W
authors.initials: DW
authors.lastname: Harshaw
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000276:immunology; D014018:Tissue Distribution; D010959:Tissue Plasminogen Activator / Q000378:metabolism*
chemical_list: D000906:Antibodies; D005343:Fibrinolytic Agents; D018799:Intercellular Adhesion Molecule-1; D010959:Tissue Plasminogen Activator