An ultrasound-responsive nano delivery system of tissue-type plasminogen activator for thrombolytic therapy
An ultrasound-responsive nano delivery system of tissue-type plasminogen activator for thrombolytic therapy
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DOI：
10.1016/j.jconrel.2010.07.127
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发表时间：
2010-10-15
影响因子：
10.8
通讯作者：
Tabata, Yasuhiko
中科院分区：
文献类型：
--
作者：
Uesugi, Yoshiko;Kawata, Hiroyuki;Tabata, Yasuhiko
本研究设计了一种新型的组织型纤溶酶原激活剂（t-PA）纳米给药系统，该系统具有抑制t-PA的溶栓活性，但只有在超声作用下才能恢复其活性。将不同量的乙二胺化学引入明胶（阳离子化明胶）中以与t-PA络合。为了用聚乙二醇（PEG）修饰复合物的表面，将PEG化学接枝到阴离子明胶（PEG-明胶）上。与PEG-明胶的简单混合使得t-PA-阳离子化明胶复合物能够在表面上形成具有PEG链的纳米尺寸的递送复合物。PEG修饰的复合物的t-PA活性被显著抑制至原始t-PA的45%。然而，当暴露于超声在体外，t-PA活性完全恢复。细胞培养实验证明PEG修饰的复合物没有细胞毒性。体内分布研究表明，t-PA在血液循环中的半衰期延长约3倍。在兔血栓形成模型中，静脉内施用PEG修饰的复合物，随后超声照射导致完全再通，与单独施用复合物形成鲜明对比。可以得出结论，PEG修饰的复合物是一种有前途的t-PA递送系统，以增强仅通过局部超声照射所需的位点处的生物活性。(C)2010爱思唯尔有限公司版权所有。
This study is undertaken to design a novel nano-sized delivery system of tissue-type plasminogen activator (t-PA) which has a suppressed thrombolytic activity of t-PA, but recovered the activity only when exposed to ultrasound. Various amounts of ethylenediamine were chemically introduced into gelatin (cationized gelatins) to complex with t-PA. To modify the surface of complexes with polyethylene glycol (PEG), PEG was chemically grafted to the anionic gelatin (PEG-gelatin). The simple mixing with the PEG-gelatin enabled the t-PA-cationized gelatin complex to form a nano-sized delivery complex with PEG chains on the surface. The t-PA activity of PEG-modified complexes was significantly suppressed to be 45% of original t-PA. However, when exposed to ultrasound in vitro, the t-PA activity was fully recovered. A cell culture experiment demonstrated no cytotoxicity of PEG-modified complexes. The body distribution study indicated that the half-life of t-PA in the blood circulation was prolonged about 3 times. In a rabbit thrombosis model, the intravenous administration of PEG-modified complexes followed by ultrasound irradiation resulted in complete recanalization, in remarked contrast to the complex administration alone. It is concluded that the PEG-modified complex is a promising t-PA delivery system to enhance the biological activity at the site necessary only by a local ultrasound irradiation. (C) 2010 Elsevier B.V. All rights reserved.