Sequentially Site-Specific Delivery of Thrombolytics and Neuroprotectant for Enhanced Treatment of Ischemic Stroke
Sequentially Site-Specific Delivery of Thrombolytics and Neuroprotectant for Enhanced Treatment of Ischemic Stroke
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依次定点递送溶栓剂和神经保护剂以加强缺血性中风的治疗
DOI：
10.1021/acsnano.9b01798
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发表时间：
2019
期刊：
影响因子：
17.1
通讯作者：
Hongliang Xin
中科院分区：
文献类型：
--
作者：
Jianpei Xu;Xiaoqi Wang;Haoyuan Yin;Xiang Cao;Quanyin Hu;Wei Lv;Qunwei Xu;Zhen Gu;Hongliang Xin
由血栓阻塞和缺血引起的缺血性中风是最致命和最致残的脑血管疾病之一。人们迫切需要一种顺序靶向的递送系统，将溶栓剂和神经保护剂分别递送到血栓和缺血半暗带的部位，以追求最大的联合效果。受到血小板在血栓形成中的重要作用的启发，在此，我们开发了一种生物工程“纳米血小板”(TP-NP-rtPA/ZL006e)，用于顺序地定点输送重组组织型纤溶酶原激活剂(RtPA)和神经保护剂(ZL006e)用于缺血性卒中的治疗。TP-NP-rtPA/ZL006e由负载ZL006e的葡聚糖衍生物聚合物纳米粒子核心和与凝血酶可切割的TAT多肽偶联rtPA连接的血小板膜壳组成。TP-NP-rtPA/ZL006e以血小板膜为外膜，靶向血栓部位，上调的凝血酶激活rtPA释放。随后，暴露在TAT环境中的TAT多肽促进了ZL006e位点特异性递送的“纳米血小板”穿过血脑屏障进入缺血脑中。体外和体内实验表明，TP-NP-rtPA/ZL006e能显著提高大脑中动脉闭塞大鼠模型的抗缺血性卒中效果，缺血面积和活性氧水平分别比游离药物联合用药组降低63%和72%。
Ischemic stroke caused by a thrombus clog and ischemia is one of the most lethal and disabling cerebrovascular diseases. A sequentially targeted delivery system is highly desired to deliver thrombolytics and neuroprotectant to the site of the thrombus and ischemic penumbra, respectively, to pursue a maximized combinational effect. Inspired by the vital roles that platelets play in thrombus formation, herein, we develop a bioengineered “nanoplatelet” (tP-NP-rtPA/ZL006e) for sequentially site-specific delivery of recombinant tissue plasminogen activator (rtPA) and neuroprotectant (ZL006e) for ischemic stroke treatment. The tP-NP-rtPA/ZL006e consists of a ZL006e-loaded dextran derivative polymeric nanoparticle core and platelet membrane shell conjugated with thrombin-cleavable Tat-peptide-coupled rtPA. Mediated by the cloak of the platelet membrane, tP-NP-rtPA/ZL006e targets the thrombus site and rtPA is triggered to release by the upregulated thrombin. Subsequently, thein situexposed Tat peptide enhanced penetration of the “nanoplatelet” across the blood–brain barrier into ischemic brain for ZL006e site-specific delivery. From thein vitroandin vivoevaluation, tP-NP-rtPA/ZL006e is demonstrated to significantly enhance the anti-ischemic stroke efficacy in the rat model with middle cerebral artery occlusion, showing a 63 and 72% decrease in ischemic area and reactive oxygen species level compared to that with free drug combination, respectively.