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.

ICAM-1 recycling in endothelial cells: a novel pathway for sustained intracellular delivery and prolonged effects of drugs

“…[4][5][6][7] Antibodies to ICAM-1 are being explored as therapeutics and affinity carriers in cell cultures, animal models, and early clinical studies. [8][9][10][11][12][13] In addition to acting as delivery vehicles, antibody blocking of ICAM-1 suppresses leukocyte adhesion to ECs, providing an anti-inflammatory benefit to the effects of drugs. 14,15 Targeting nanocarriers (NCs) to EC determinants decreases the clearance of drugs from the bloodstream and permits site-specific delivery, increasing therapeutic capacity and reducing side effects (Muzykantov 16 ).…”

Targeting of Drugs to ICAM for Treatment of Acute Lung Injury

“…antibodies) have been found to undergo endocytic uptake in endothelium [75,87,205,206]. However, major group human rhinovims and respiratory syncytial vims use ICAM-1 as a receptor during cell invasion, although the mechanism of cell uptake remains uncertain [207,208].…”

“…ROS and cytokines elevate the ICAM-1 surface density in pulmonary EC [90,91]. Therefore, in contrast with some other constitutive endothelial determinants (e.g., TM and' ACE), immunotargeting to ICAM-1 is not suppressed, but instead is markedly facilitated in inflammation and other pathological conditions [85][86][87][92][93][94][95][96].…”

“…However, the major fraction of blood-accessible ICAM-1 is exposed on the luminal surface of EC. Several laboratories demonstrated robust and specific binding of radiolabeled ICAM antibodies and anti-ICAM conjugates to vascular endothelium after intravenous administration in diverse laboratory animals [64,73,[85][86][87].…”

Lung Endothelium Targeting for Pulmonary Embolism Thrombolysis

“…9,10 As an alternative strategy, tissue-preferential mAb has been also developed to retain thrombolysis locally, especially for the case of PE thrombolysis to avert hemorrhagic complications. Murciano et al 11 recently illustrated in rats that intercellular adhesion molecule-1 was suitable to target tPA to the pulmonary vascular lumen, in addition to their previous work showing that the conjugate of plasminogen activator with anti-ACE mAb provided preferential targeting to the pulmonary vasculature. 12 A lung surfactant protein, SP-B, and an mAb against SP-B chemically cross-linked to UK were also reported for targeting alveolar fibrin.…”