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

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 6; p. 2578
• Main Authors: Chen, Shuangling, Liang, Meng, Wu, Chengli, Zhang, Xiaoyi, Wang, Yuji, Zhao, Ming
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.03.2023; MDPI
• Subjects: Animals; Biodegradability; Biodegradation; Bleeding; Blood clots; Dosage; Drug delivery; Drug dosages; Fibrin; Fibrinolytic Agents - pharmacology; Fibrinolytic Agents - therapeutic use; Hemorrhage; In vitro methods and tests; L-aspartyl; Ligands; Lysis; Medical research; nano delivery system; Nanoparticles; Peptides; Rats; RGDS; Side effects; targeted; Thromboembolism; Thrombolysis; thrombolytic; Thrombolytic Therapy; Thrombosis; Thrombosis - drug therapy; U-Plasminogen activator; Urokinase; Urokinase-Type Plasminogen Activator; United Kingdom > UK; targeted; RGDS; nano delivery system; thrombolytic; urokinase
• ISSN: 1420-3049; 1420-3049
• 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.