School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
Molecules. 2023 Mar 12;28(6):2578. doi: 10.3390/molecules28062578.
The most concerning adverse effects of thrombolytic agents are major bleeding and intracranial hemorrhage due to their short half-life, low fibrin specificity, and high dosage. To alleviate bleeding side effects during thrombolytic therapy which would bring about the risk of aggravation, we try to find a novel biodegradable delivery nanosystem to carry drugs to target the thrombus, reduce the dosage of the drug, and system side effects. A novel urokinase/poly-, -, -aspartyl-Arg-Gly-Asp-Ser complex (UK/PD-RGDS) was synthesized and simply prepared. Its thrombolytic potency was assayed by the bubble-rising method and in vitro thrombolytic activity by the thrombus clot lysis assay separately. The in vivo thrombolytic activity and bleeding complication were evaluated by a rat model of carotid arteriovenous bypass thrombolysis. The thrombolytic potency (1288.19 ± 155.20 U/mg) of the UK/PD-RGDS complex nano-globule (18-130 nm) was 1.3 times that of commercial UK (966.77 ± 148.08 U/mg). In vivo, the UK/PD-RGDS complex (2000 IU/kg) could reduce the dose of UK by 90% while achieving the equivalent thrombolysis effect as the free UK (20,000 IU/kg). Additionally, the UK/PD-RGDS complex decreased the tail bleeding time compared with UK. The organ distribution of the FITC-UK/PD-RGDS complex was explored in the rat model. The UK/PD-RGDS complex could provide a promising platform to enhance thrombolytic efficacy significantly and reduce the major bleeding degree.
溶栓药物最令人关注的不良反应是大出血和颅内出血，这是由于它们半衰期短、纤维蛋白特异性低、剂量高。为了减轻溶栓治疗过程中的出血副作用，从而带来加重的风险，我们试图寻找一种新型的可生物降解的递药纳米系统，将药物靶向输送至血栓部位，减少药物剂量和全身副作用。我们合成了一种新型的尿激酶/聚（天冬氨酸-精氨酸-甘氨酸-丝氨酸）（UK/PD-RGDS）复合物，并对其进行了简单的制备。通过气泡上升法和血栓溶解试验分别测定其溶栓活性和体外溶栓活性。通过颈动脉动静脉旁路溶栓大鼠模型评估其体内溶栓活性和出血并发症。UK/PD-RGDS 复合纳米球（18-130nm）的溶栓效力（1288.19±155.20U/mg）是商品化 UK（966.77±148.08U/mg）的 1.3 倍。在体内，UK/PD-RGDS 复合物（2000IU/kg）可使 UK 的剂量减少 90%，同时达到与游离 UK（20000IU/kg）相当的溶栓效果。此外，UK/PD-RGDS 复合物与 UK 相比，可减少尾部出血时间。在大鼠模型中探讨了 FITC-UK/PD-RGDS 复合物的器官分布。UK/PD-RGDS 复合物为显著提高溶栓疗效和降低大出血程度提供了一个有前景的平台。
