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

作　　者：王纯[1] 肖建[1] 刘阳[1] Chun Wang;Jian Xiao;Yang Liu(Key Laboratory of Functional Polymer Material,Department of Chemistry,Nankai University,Tianjin 300071)

机构地区：[1]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

出　　处：《高分子学报》2024年第1期27-35,共9页Acta Polymerica Sinica

基　　金：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。

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.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 

分 类 号：TB383.1[一般工业技术—材料科学与工程] TQ460.1[化学工程—制药化工] R543[医药卫生—心血管疾病]