A New Drug Delivery System for Intravenous Coronary Thrombolysis With Thrombus Targeting and Stealth Activity Recoverable by Ultrasound
A New Drug Delivery System for Intravenous Coronary Thrombolysis With Thrombus Targeting and Stealth Activity Recoverable by Ultrasound
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DOI：
10.1016/j.jacc.2012.08.1008
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发表时间：
2012-12-18
影响因子：
24
通讯作者：
Saito, Yoshihiko
中科院分区：
文献类型：
--
作者：
Kawata, Hiroyuki;Uesugi, Yoshiko;Saito, Yoshihiko
目的本研究旨在开发一种新型的智能化冠状动脉内溶栓给药系统，在不增加出血风险的情况下，具有较强的溶栓效果。以导管为基础的再通被广泛接受，但运送病人需要时间。目前的纤溶治疗虽然可以快速开始，但不能达到很高的再通率。最近，我们合成了含有组织型纤溶酶原激活剂(TPA)、碱性明胶和锌离子的纳米颗粒，在体外通过超声(US)抑制tPA活性50%，恢复100%。方法采用von Wilbrand因子体外结合试验和体内小鼠动脉血栓形成模型检测纳米颗粒的血栓靶向性。用猪急性心肌梗死模型评价纳米粒的溶栓效果。结果纳米粒在体外与von Wilbrand因子结合，并在小鼠模型血栓处优先蓄积。在猪急性心肌梗死模型中，静脉注射纳米颗粒后，血浆tPA活性约为单独注射tPA的25%，经胸超声(1.0 MHz，1.0W/cm(2))完全恢复。超声作用期间，受累冠状动脉附近的血浆tPA活性恢复，且高于股动脉附近。单用tPA(55000IU/kg)治疗10只猪中只有1只再通闭塞的冠状动脉，但含有与US相同剂量的tPA纳米粒可在30分钟内再通9只猪。结论我们开发的智能给药系统具有更好的静脉溶栓潜力。(J Am Coll心脏ol 2012；60：2550-7)(C)2012，美国心脏病学会基金会
Objectives The purpose of this study was to develop a new intelligent drug delivery system for intracoronary thrombolysis with a strong thrombolytic effect without increasing bleeding risk.BackgroundRapid recanalization of an occluded coronary artery is essential for better outcomes in acute myocardial infarction. Catheter-based recanalization is widely accepted, but it takes time to transport patients. Although the current fibrinolytic therapy can be started quickly, it cannot achieve a high reperfusion rate. Recently, we generated nanoparticles comprising tissue-type plasminogen activator (tPA), basic gelatin, and zinc ions, which suppress tPA activity by 50% with 100% recovery by ultrasound (US) in vitro.MethodsThe thrombus-targeting property of nanoparticles was examined by an in vitro binding assay with von Wilbrand factor and with a mouse arterial thrombosis model in vivo. The thrombolytic efficacy of nanoparticles was evaluated with a swine acute myocardial infarction model.ResultsNanoparticles bound to von Wilbrand factor in vitro and preferentially accumulated at the site of thrombus in a mouse model. In a swine acute myocardial infarction model, plasma tPA activity after intravenous injection of nanoparticles was approximately 25% of tPA alone and was recovered completely by transthoracic US (1.0 MHz, 1.0 W/cm(2)). During US application, plasma tPA activity near the affected coronary artery was recovered and was higher than that near the femoral artery. Although treatment with tPA alone (55,000 IU/kg) recanalized the occluded coronary artery in only 1 of 10 swine, nanoparticles containing the same dose of tPA with US achieved recanalization in 9 of 10 swine within 30 min.ConclusionsWe developed an intelligent drug delivery system with promising potential for better intravenous coronary thrombolysis. (J Am Coll Cardiol 2012; 60:2550-7) (C) 2012 by the American College of Cardiology Foundation