Combination of Polyethylene Glycol-Conjugated Urokinase Nanogels and Urokinase for Acute Ischemic Stroke Therapeutic Implications
Combination of Polyethylene Glycol-Conjugated Urokinase Nanogels and Urokinase for Acute Ischemic Stroke Therapeutic Implications
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DOI：
10.1007/s12975-020-00865-2
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发表时间：
2020-10-16
影响因子：
6.9
通讯作者：
Huang, Yining
中科院分区：
文献类型：
--
作者：
Nan, Ding;Jin, Haiqiang;Huang, Yining
组织再灌注是缺血性卒中除血管再通外的重要治疗策略。在这项工作中，我们的目的是建立新的尿激酶为基础的治疗，以溶解大血管血栓与微血栓中风的影响。对由游离尿激酶（UK）、聚乙二醇交联尿激酶纳米凝胶（PEG-UK）以及UK和PEG-UK的1：1混合物（PEG-UK+UK）组成的制剂进行了体外和体内测试。体外实验证实了PEG-UK+UK制剂中PEG-UK的pH依赖性释放。由于PEG-UK的动态交联特性，它在梗塞脑组织中的环境pH 6.50下被激活。在血栓栓塞性中风大鼠模型上的体内试验表明，含有UK的制剂，即，游离UK和PEG-UK+UK在时间窗内表现出更好的神经学评分和更小的梗死体积，其中PEG-UK+UK制剂相对表现更好。另一方面，含有PEG-UK，即，PEG-UK和PEG-UK+UK在时间窗外获得足够的溶栓效率。进一步的机制研究表明，PEG-UK可减少远端微循环中的微血栓，其破坏作用也小于游离UK。PEG-UK+UK制剂实际上提供了UK向大血管和微循环的“双靶向”递送，这在治疗时间窗内和治疗时间窗外均有利于治疗缺血性脑卒中。
Tissue reperfusion is a serious therapeutic strategy of ischemic stroke in addition to recanalization. In this work, we aimed to establish new urokinase-based therapeutics in order to dissolve large vessel thrombus together with microthrombi for stroke implications. Formulations consisted of free urokinase (UK), polyethylene glycol-crosslinked urokinase nanogel (PEG-UK), and a 1:1 mixture of UK and PEG-UK (PEG-UK+UK) were tested both in vitro and in vivo. In vitro experiments confirmed the pH-dependent release of PEG-UK in the PEG-UK+UK formulation. It was activated at pH 6.50, an environmental pH in the infarct brain tissue, owing to the dynamic crosslink property of PEG-UK. In vivo tests on a thromboembolic stroke rat model showed that the formulations containing UK, i.e., free UK and PEG-UK+UK, demonstrated better neurological scores and smaller infarction volumes within the time window, in which the PEG-UK+UK formulation relatively performed better. On the other hand, the formulations containing PEG-UK, i.e., PEG-UK and PEG-UK+UK, gained sufficient thrombolytic efficiency beyond the time window. Further investigation on the mechanism revealed that PEG-UK could reduce microthrombus in distal microcirculation, and its destructive effect was also less than that of free UK. The PEG-UK+UK formulation actually provided a "dual targeting" delivery of UK to both the large vessels and the microcirculation, which was beneficial to the treatment of cerebral ischemic stroke both within and beyond the therapeutic time window.