ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface
ICAM-directed vascular immunotargeting of antithrombotic agents to the endothelial luminal surface
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DOI：
10.1182/blood-2002-09-2853
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发表时间：
2003-05-15
期刊：
影响因子：
20.3
通讯作者：
Muzykantov, VR
中科院分区：
文献类型：
--
作者：
Murciano, JC;Muro, S;Muzykantov, VR
药物靶向一个高度表达的，非内化的决定因素在受干扰的内皮细胞上上调，可能有助于控制炎症和血栓形成。我们测试了细胞间粘附分子-1 （ICAM-1）靶向是否适合将抗血栓药物输送到肺血管管腔。ICAM-1抗体结合内皮细胞表面，在培养，灌注肺和体内。促炎细胞因子增强抗icam与内皮的结合而不诱导内化。i- 125标记的抗icam和与抗icam结合的报告酶（P-Gal）在大鼠和小鼠静脉给药后与内皮细胞结合并在肺部积聚。电镜显示，抗- icam主要定位于肺内皮的管腔表面。我们研究了icam定向靶向组织型纤溶酶原激活剂（tPA）的药理作用。抗icam /tPA偶联物在大鼠肺中积累，发挥纤溶酶原激活剂活性，溶解纤维蛋白微栓子，但不控制IgG/tPA。因此，ICAM可以作为药物递送到内皮细胞的靶点，例如用于肺血栓预防。增强对炎症部位的药物递送和阻断ICAM-1的潜在抗炎作用可能会增强这种靶向策略的益处。(C) 2003年由美国血液病学会出版。
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 endotheliall cells in culture, in perfused lungs, and in vivo. Proinflammatory cytokines enhance anti-ICAM binding to the endothelium without inducing internalization. I-125-labeled anti-ICAM and a reporter enzyme (P-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. (C) 2003 by The American Society of Hematology.