共递送尿激酶和替格瑞洛的纳米递送系统用于血栓疾病治疗的研究

王纯; 肖建; 刘阳

doi:10.11777/j.issn1000-3304.2023.23167

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共递送尿激酶和替格瑞洛的纳米递送系统用于血栓疾病治疗的研究

研究论文 | 更新时间：2024-01-03

- 共递送尿激酶和替格瑞洛的纳米递送系统用于血栓疾病治疗的研究
- Thrombus Targeted Delivery of Urokinase and Ticagrelor for Thrombosis-related Diseases Treatment
- 高分子学报 2024年55卷第1期页码：27-35
- 作者机构：
  
  功能高分子材料教育部重点实验室南开大学化学系天津 300071
- 作者简介：
  
  Yang Liu, E-mail: yliu@nankai.edu.cn
- 基金信息：
  
  国家自然科学基金(基金号 22077073);双一流高校建设经费(南开大学, 项目号 63206015)资助项目
- DOI：10.11777/j.issn1000-3304.2023.23167
  中图分类号：
- 纸质出版日期：2024-01-20，
  
  网络出版日期：2023-10-26，
  
  收稿日期：2023-06-25，
  
  录用日期：2023-08-25
- 稿件说明：
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王纯, 肖建, 刘阳. 共递送尿激酶和替格瑞洛的纳米递送系统用于血栓疾病治疗的研究. 高分子学报, 2024, 55(1), 27-35

Wang, C.; Xiao, J.; Liu, Y. Thrombus targeted delivery of urokinase and ticagrelor for thrombosis-related diseases treatment. Acta Polymerica Sinica, 2024, 55(1), 27-35
王纯, 肖建, 刘阳. 共递送尿激酶和替格瑞洛的纳米递送系统用于血栓疾病治疗的研究. 高分子学报, 2024, 55(1), 27-35 DOI： 10.11777/j.issn1000-3304.2023.23167.

Wang, C.; Xiao, J.; Liu, Y. Thrombus targeted delivery of urokinase and ticagrelor for thrombosis-related diseases treatment. Acta Polymerica Sinica, 2024, 55(1), 27-35 DOI： 10.11777/j.issn1000-3304.2023.23167.

摘要

设计合成了一种可靶向血栓部位进行共递送尿激酶和替格瑞洛的纳米粒子(PEG-LCN-uPA)，其内核为负载抗血小板药物替格瑞洛的可变形液体纳米粒子(LCN)，表面为通过缩酮连接臂修饰的溶栓药物尿激酶和具有靶向功能的聚合物链PEG-CREKA. 得益于LCN的高渗透性和缩酮连接臂的氧化应激响应性，该纳米粒子经静脉注射后可在血液循环中保持稳定，经循环到达血栓部位后可高效渗透并累积至血栓部位，并响应氧化应激微环境释放尿激酶和替格瑞洛. 最终，在小鼠颈动脉血栓模型和小鼠尾部血栓模型中，PEG-LCN-uPA均实现了安全有效的溶栓效果，展现了治疗血栓相关疾病的潜力.

Abstract

Thrombus related diseases seriously threaten human health. A variety of thrombolytic drugs and antiplatelet agents have been used for the treatment of thrombus related diseases. However

the short circulation half-life

narrow therapeutic window and high bleeding risks seriously restrict their therapeutic effects. To achieve safe and effective thrombolytic therapy

we herein developed a kind of novel nanomaterial to codeliver thrombolytic drug urokinase (uPA) and antiplatelet agent ticagrelor for targeted thrombolysis. Based on the liquid core nanoparticles (LCN)

we first loaded ticagrelor in LCN

followed by modification of uPA and poly(ethylene glycol)-Cys-Arg-Glu-Lys-Ala (PEG-CREKA) on the surface with thioketal linker to obtain PEG-LCN-uPA. PEG-LCN-uPA exhibited effective thrombolysis only in high oxidative microenvironment

indicating its potential for thrombolysis without causing bleeding. Furthermore

owing to the thrombus targeting ability of CREKA peptide

PEG-LCN-uPA achieved effective targeting and accumulation at thrombus site after intravenous injection. Moreover

the thioketal linker was used to conjugate LCN and uPA degraded in response to the oxidative microenvironment at thrombus site

resulting in the release of uPA for further thrombolysis. In the meantime

the detachment of PEG-CREKA allowed the release of ticagrelor for antiplatelet therapy. Animal studies indicated that PEG-LCN-uPA exhibited effective thrombolysis in both mice tail thrombus models and carotid arterial thrombosis model without obvious safety issues. The decrease of sCD40L level indicated the effective reduced activation of platelet

which benefits for long-term antithrombus therapy. With these abilities

PEG-LCN-uPA presented its potential as a feasible strategy for thrombosis-related diseases treatment.

关键词

纳米材料血栓抗血小板尿激酶氧化应激

Keywords

NanomaterialsThrombusAntiplateletUrokinaseOxidative stress

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