Wang Ying, Xu Xiaowen, Zhao Xuan, Yin Zongning
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Acta Biomater. 2021 Mar 1;122:278-290. doi: 10.1016/j.actbio.2020.10.015. Epub 2020 Dec 25.
Pathological thrombosis within a vessel hampers blood flow and is the mainspring of numerous fatal cardiovascular complications. In order to specifically image and dissolve a thrombus, we rationally designed a functionalized polymeric hybrid micelle (PHM) system self-assembled from amphiphilic polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethylene glycol (PCL-PEG). Based on a biological component of thrombi, activated coagulation factor XIII (FXIIIa), which is responsible for fibrin crosslinking, we further developed FXIIIa-targeted near infrared imaging and thrombolytic nanoparticles, termed IR780/FPHM/LK NPs, through chemical conjugation of peptides to the system. In a ferric chloride (FeCl)-induced mouse carotid thrombosis model, IR780/FPHM/LK NPs specifically targeted the thrombus and significantly enhanced the photoacoustic signal for an accurate diagnosis. When loaded with the fibrinolytic drug lumbrokinase (LK), FPHM remarkably dissociated the thrombus accompanied by an increase in the d-dimer level, a fibrin degradation product, and alleviation of fatal nonspecific hemorrhagic risk. Given its thrombus-specific imaging along with potent therapeutic activities, IR780/FPHM/LK NPs hold promise for developing nanotheranostic agents in preclinical thrombotic vascular disease models.
血管内的病理性血栓会阻碍血液流动，是众多致命心血管并发症的根源。为了特异性地成像和溶解血栓，我们合理设计了一种由两亲性聚己内酯 - 聚乙烯亚胺（PCL - PEI）和聚己内酯 - 聚乙二醇（PCL - PEG）自组装而成的功能化聚合物杂化胶束（PHM）系统。基于血栓的一种生物成分，即负责纤维蛋白交联的活化凝血因子 XIII（FXIIIa），我们通过将肽化学偶联到该系统，进一步开发了靶向 FXIIIa 的近红外成像和溶栓纳米颗粒，称为 IR780/FPHM/LK NPs。在氯化铁（FeCl）诱导的小鼠颈动脉血栓形成模型中，IR780/FPHM/LK NPs 特异性地靶向血栓，并显著增强光声信号以进行准确诊断。当负载纤溶药物蚓激酶（LK）时，FPHM 显著溶解血栓，同时纤维蛋白降解产物 D - 二聚体水平升高，并减轻致命的非特异性出血风险。鉴于其对血栓的特异性成像以及强大的治疗活性，IR780/FPHM/LK NPs 在临床前血栓性血管疾病模型中开发纳米诊疗剂方面具有前景。
