A fibrin-specific thrombolytic nanomedicine approach to acute ischemic stroke.
A fibrin-specific thrombolytic nanomedicine approach to acute ischemic stroke.
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DOI：
10.2217/nnm.11.21
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Lanza GM
中科院分区：
文献类型：
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作者：
Marsh JN;Hu G;Scott MJ;Zhang H;Goette MJ;Gaffney PJ;Caruthers SD;Wickline SA;Abendschein D;Lanza GM
开发纤维蛋白特异性尿激酶纳米药物溶栓剂。利用体外纤维蛋白凝块溶解研究来开发和表征抗纤维蛋白单克隆抗体和尿激酶在全氟化碳纳米颗粒 (NP) 表面上的同时偶联和负载。在狗身上研究了纳米溶解剂的体内药代动力学和纤维蛋白特异性靶向。每个全氟化碳纳米颗粒同时偶联多达 40 种抗纤维蛋白抗体和 400 种尿激酶，产生了一种有效的靶向纳米溶解剂，且没有明显的表面蛋白-蛋白干扰。通过将归巢能力从 10 个抗体/NP 增加到 40 个抗体/NP，纤维蛋白凝块溶解并没有得到改善，但将酶有效负载从 100 个/NP 增加到 400 个/NP 导致溶解效果最大化。荧光显微镜显示，罗丹明标记的尿激酶纳米颗粒在体内密集地修饰了犬类凝块中的腔内血栓，类似于纤维蛋白模式，而不相关的靶向药物的结合可以忽略不计。该药物提供了一种血管受限、易于管理、低剂量的纳米药物方法，可能为治疗急性中风患者提供一种有吸引力的替代方案。
To develop a fibrin-specific urokinase nanomedicine thrombolytic agent. In vitro fibrin-clot dissolution studies were utilized to develop and characterize simultaneous coupling and loading of anti-fibrin monoclonal antibody and urokinase onto perfluorocarbon nanoparticle (NP) surface. In vivo pharmacokinetics and fibrin-specific targeting of the nanolytic agent was studied in dogs. Simultaneous coupling of up to 40 anti-fibrin antibodies and 400 urokinase enzymes per perfluorocarbon NP produced an effective targeted nanolytic agent with no significant surface protein–protein interference. Fibrin clot dissolution was not improved by increasing homing capacity from 10 to 40 antibodies/NP, but increasing enzymatic payload from 100 to 400/NP resulted in maximized lytic effect. Fluorescent microscopy showed that rhodamine-labeled urokinase nanoparticles densely decorated the intraluminal thrombus in canine clots in vivo analogous to the fibrin pattern, while an irrelevant-targeted agent had negligible binding. This agent offers a vascularly constrained, simple to administer, low-dose nanomedicine approach that may present an attractive alternative for treating acute stroke victims.