Poly-α, β-d, l-Aspartyl-Arg-Gly-Asp-Ser-Based Urokinase Nanoparticles for Thrombolysis Therapy

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-alpha, beta-d, l-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.

Automated summary

In order to mitigate the bleeding side effects during thrombolytic therapy, a novel biodegradable nanosystem was developed to deliver drugs specifically to the thrombus. The UK/PD-RGDS complex nano-globule showed 1.3 times higher thrombolytic potency compared to commercial UK. In vivo experiments demonstrated that the UK/PD-RGDS complex could achieve equivalent thrombolysis with a 90% reduction in UK dosage.