Université de Paris, Université Sorbonne Paris Nord, UMR S1148, INSERM, F-75018, Paris, France.
INSERM U1237 Physiopathology and Imaging of Neurological Disorders (PhIND), Institut Blood and Brain @ Caen Normandie (BB@C), GIP Cyceron, 14074, Caen, France.
Biomaterials. 2021 Oct;277:121102. doi: 10.1016/j.biomaterials.2021.121102. Epub 2021 Aug 30.
Intravenous administration of fibrinolytic drugs is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and might trigger hemorrhagic transformations. Therefore, it is mandatory to develop innovative nanomedicine-based solutions for more efficient and safer thrombolysis with biocompatible and biodegradable thrombus-targeted nanocarrier. Herein, fucoidan-functionalized hydrogel polysaccharide submicroparticles with high biocompatibility are elaborated by the inverse miniemulsion/crosslinking method. They are loaded with the gold standard fibrinolytic - alteplase - to direct site-specific fibrinolysis due to nanomolar interactions between fucoidan and P-selectin overexpressed on activated platelets and endothelial cells in the thrombus area. The thrombus targeting properties of these particles are validated in a microfluidic assay containing recombinant P-selectin and activated platelets under arterial and venous blood shear rates as well as in vivo. The experiments on the murine model of acute thromboembolic ischemic stroke support this product's therapeutic efficacy, revealing a faster recanalization rate in the middle cerebral artery than with free alteplase, which reduces post-ischemic cerebral infarct lesions and blood-brain barrier permeability. Altogether, this proof-of-concept study demonstrates the potential of a biomaterial-based targeted nanomedicine for the precise treatment of acute thrombotic events, such as ischemic stroke.
静脉内给予纤维蛋白溶解药物是急性血栓性疾病的标准治疗方法。然而，由于目前的纤维蛋白溶解剂半衰期短，可能引发出血性转化，其临床疗效有限。因此，开发创新的基于纳米医学的解决方案，对于更有效和更安全的溶栓治疗，使用生物相容性和可生物降解的血栓靶向纳米载体，是非常必要的。在此，通过反相细乳液/交联法详细阐述了具有高生物相容性的岩藻聚糖功能化水凝胶多糖亚微米颗粒。它们负载金标准纤维蛋白溶解剂 - 阿替普酶，由于岩藻聚糖与血栓区域中激活的血小板和内皮细胞上过表达的 P-选择素之间的纳米摩尔相互作用，可直接进行靶向特定部位的纤维蛋白溶解。在含有重组 P-选择素和激活血小板的微流控测定中以及体内验证了这些颗粒的血栓靶向特性，模拟了动脉和静脉血流剪切率。在急性血栓栓塞性缺血性中风的小鼠模型上的实验支持了该产品的治疗效果，表明其在大脑中动脉的再通率比游离阿替普酶更快，从而减少了缺血性脑梗死损伤和血脑屏障通透性。总的来说，这项概念验证研究表明，基于生物材料的靶向纳米医学在精确治疗急性血栓性事件（如缺血性中风）方面具有潜力。
