Platelet-Mimicking Nanosponges for Functional Reversal of Antiplatelet Agents.
Platelet-Mimicking Nanosponges for Functional Reversal of Antiplatelet Agents.
复制标题
模拟血小板纳米海绵用于逆转抗血小板药物的功能
DOI：
10.1161/circresaha.122.321034
复制
发表时间：
2023-02-03
影响因子：
20.1
通讯作者：
Nie, Guangjun
中科院分区：
文献类型：
--
作者：
Xu, Junchao;Yan, Na;Wang, Chunling;Gao, Chao;Han, Xuexiang;Yang, Chengzhi;Xu, Jiaqi;Wang, Kun;Mitchell, Michael J. J.;Zhang, Yinlong;Nie, Guangjun
关键词：
背景资料：在长期使用抗血小板药物（APAs）期间，血栓性疾病患者发生危及生命的出血的风险相当高，特别是在需要紧急手术时。由于临床上缺乏特异性逆转剂，APA的快速功能逆转仍然是一个尚未有效解决的问题，这极大地限制了APA的使用。研究方法：首先应用流式细胞术分析来评估血小板模拟全氟化碳基纳米海绵（PLT-PFC）对替格瑞洛的剂量依赖性逆转活性。在不同的时间点记录用APA接着PLT-PFC处理的小鼠的尾部出血时间，沿着替格瑞洛和替罗非班的相应药代动力学分析。用溶栓/抗血小板治疗建立了实验性脑卒中小鼠出血性转化模型。随后应用磁共振成像观察体内出血和血栓形成。通过体外凝块收缩试验进一步评价PLT-PFCs的自发凝块形成活性。结果：PLT-PFCs通过与APAs竞争性结合而有效地逆转APAs的抗血小板作用。PLT-PFCs在体外与一线APA、替格瑞洛和替罗非班显示出与新鲜血小板相当的高结合亲和力，并在尾部出血和缺血后再灌注模型中有效地逆转了它们的功能。此外，血小板固有血栓形成活性的缺乏降低了血栓形成的风险。结论：这项研究证明了血小板模拟纳米海绵在改善不同APA的出血风险方面的安全性和有效性，这为抗血小板治疗诱导的出血并发症的管理提供了一种有前途的策略。
Background: During long-term antiplatelet agents (APAs) administration, patients with thrombotic diseases take a fairly high risk of life-threatening bleeding, especially when in need of urgent surgery. Rapid functional reversal of APAs remains an issue yet to be efficiently resolved by far due to the lack of any specific reversal agent in the clinic, which greatly restricts the use of APAs. Methods: Flow cytometry analysis was first applied to assess the dose-dependent reversal activity of platelet-mimicking perfluorocarbon-based nanosponges (PLT-PFCs) toward ticagrelor. The tail bleeding time of mice treated with APAs followed by PLT-PFCs was recorded at different time points, along with corresponding pharmacokinetic analysis of ticagrelor and tirofiban. A hemorrhagic transformation model was established in experimental stroke mice with thrombolytic/antiplatelet therapy. Magnetic resonance imaging was subsequently applied to observe hemorrhage and thrombosis in vivo. Further evaluation of the spontaneous clot formation activity of PLT-PFCs was achieved by clot retraction assay in vitro. Results: PLT-PFCs potently reversed the antiplatelet effect of APAs by competitively binding with APAs. PLT-PFCs showed high binding affinity comparable to fresh platelets in vitro with first-line APAs, ticagrelor and tirofiban, and efficiently reversed their function in both tail bleeding and postischemic-reperfusion models. Moreover, the deficiency of platelet intrinsic thrombotic activity diminished the risk of thrombogenesis. Conclusions: This study demonstrated the safety and effectiveness of platelet-mimicking nanosponges in ameliorating the bleeding risk of different APAs, which offers a promising strategy for the management of bleeding complications induced by antiplatelet therapy.