SCAMT Laboratory , ITMO University , Saint Petersburg , 191002 , Russian Federation.
Blokhin National Medical Center of Oncology , Moscow , 115478 , Russian Federation.
ACS Appl Mater Interfaces. 2018 Oct 31;10(43):36764-36775. doi: 10.1021/acsami.8b14790. Epub 2018 Oct 22.
Mortality and disabilities as outcomes of cardiovascular diseases are primarily related to blood clotting. Optimization of thrombolytic drugs is aimed at the prevention of side effects (in particular, bleeding) associated with a disbalance between coagulation and anticoagulation caused by systemically administered agents. Minimally invasive and efficient approaches to deliver the thrombolytic agent to the site of clot formation are needed. Herein, we report a novel nanocomposite prepared by heparin-mediated cross-linking of urokinase with magnetite nanoparticles (MNPs@uPA). We showed that heparin within the composition evoked no inhibitory effects on urokinase activity. Importantly, the magneto-control further increased the thrombolytic efficacy of the composition. Using our nanocomposition, we demonstrated efficient lysis of experimental clots in vitro and in animal vessels followed by complete restoration of blood flow. No sustained toxicity or hemorrhagic complications were registered in rats and rabbits after single bolus i.v. injection of therapeutic doses of MNPs@uPA. We conclude that MNPs@uPA is a prototype of easy-to-prepare, inexpensive, biocompatible, and noninvasive thrombolytic nanomedicines potentially useful in the treatment of blood clotting.
心血管疾病的死亡和残疾主要与血栓形成有关。溶栓药物的优化旨在预防与全身性给药制剂引起的凝血和抗凝失衡相关的副作用（特别是出血）。需要微创且有效的方法将溶栓剂递送到血栓形成部位。在此，我们报告了一种通过肝素介导的尿激酶与磁铁矿纳米颗粒（MNPs@uPA）交联制备的新型纳米复合材料。我们表明，该组合物中的肝素对尿激酶活性没有抑制作用。重要的是，磁控进一步提高了该组合物的溶栓效果。使用我们的纳米复合材料，我们证明了在体外和动物血管中有效溶解实验性血栓，随后完全恢复血流。在大鼠和兔单次静脉注射治疗剂量的 MNPs@uPA 后，未观察到持续的毒性或出血并发症。我们得出结论，MNPs@uPA 是一种易于制备、廉价、生物相容且非侵入性的溶栓纳米药物的原型，可能对治疗血栓形成有用。
