INSERM, U1148, Laboratory for Vascular Translational Science, X. Bichat Hospital, 46 rue Henri Huchard, 75018, Paris, France; Paris Diderot University, Paris 13 University, Sorbonne Paris Cité, Paris, France.
INSERM, U1148, Laboratory for Vascular Translational Science, X. Bichat Hospital, 46 rue Henri Huchard, 75018, Paris, France; Paris Diderot University, Paris 13 University, Sorbonne Paris Cité, Paris, France; FRIM, INSERM UMS 034 Paris Diderot University, X. Bichat Hospital, 75018, Paris, France.
Biomaterials. 2018 Feb;156:204-216. doi: 10.1016/j.biomaterials.2017.11.047. Epub 2017 Nov 29.
Injection of recombinant tissue plasminogen activator (rt-PA) is the standard drug treatment for thrombolysis. However, rt-PA shows risk of hemorrhages and limited efficiency even at high doses. Polysaccharide-poly(isobutylcyanoacrylate) nanoparticles functionalized with fucoidan and loaded with rt-PA were designed to accumulate on the thrombus. Fucoidan has a nanomolar affinity for the P-selectin expressed by activated platelets in the thrombus. Solid spherical fluorescent nanoparticles with a hydrodynamic diameter of 136 ± 4 nm were synthesized by redox radical emulsion polymerization. The clinical rt-PA formulation was successfully loaded by adsorption on aminated nanoparticles and able to be released in vitro. We validated the in vitro fibrinolytic activity and binding under flow to both recombinant P-selectin and activated platelet aggregates. The thrombolysis efficiency was demonstrated in a mouse model of venous thrombosis by monitoring the platelet density with intravital microscopy. This study supports the hypothesis that fucoidan-nanoparticles improve the rt-PA efficiency. This work establishes the proof-of-concept of fucoidan-based carriers for targeted thrombolysis.
注射重组组织型纤溶酶原激活剂（rt-PA）是溶栓的标准药物治疗方法。然而，即使在高剂量下，rt-PA 也显示出出血风险和有限的效率。用岩藻聚糖修饰的多糖-聚异丁基氰基丙烯酸酯纳米粒子并负载 rt-PA 被设计用于在血栓上聚集。岩藻聚糖对血栓中活化血小板表达的 P-选择素有纳摩尔亲和力。通过氧化还原自由基乳液聚合合成了具有 136±4nm 水动力直径的固态球形荧光纳米粒子。通过吸附在氨基化纳米粒子上成功负载了临床用 rt-PA 制剂，并能够在体外释放。我们验证了在重组 P-选择素和活化血小板聚集体下的体外纤维蛋白溶解活性和流动结合。通过活体显微镜监测血小板密度，在静脉血栓形成的小鼠模型中证明了溶栓效率。这项研究支持了岩藻聚糖纳米粒子提高 rt-PA 效率的假设。这项工作为基于岩藻聚糖的靶向溶栓载体建立了概念验证。
