Thrombus Targeted Delivery of Urokinase and Ticagrelor for Thrombosis-related Diseases Treatment
Thrombus related diseases seriously threaten human health.A variety of thrombolytic drugs and antiplatelet agents have been used for the treatment of thrombus related diseases.However,the short circulation half-life,narrow therapeutic window and high bleeding risks seriously restrict their therapeutic effects.To achieve safe and effective thrombolytic therapy,we herein developed a kind of novel nanomaterial to codeliver thrombolytic drug urokinase(uPA)and antiplatelet agent ticagrelor for targeted thrombolysis.Based on the liquid core nanoparticles(LCN),we first loaded ticagrelor in LCN,followed by modification of uPA and poly(ethylene glycol)-Cys-Arg-Glu-Lys-Ala(PEG-CREKA)on the surface with thioketal linker to obtain PEG-LCN-uPA.PEG-LCN-uPA exhibited effective thrombolysis only in high oxidative microenvironment,indicating its potential for thrombolysis without causing bleeding.Furthermore,owing to the thrombus targeting ability of CREKA peptide,PEG-LCN-uPA achieved effective targeting and accumulation at thrombus site after intravenous injection.Moreover,the thioketal linker was used to conjugate LCN and uPA degraded in response to the oxidative microenvironment at thrombus site,resulting in the release of uPA for further thrombolysis.In the meantime,the detachment of PEG-CREKA allowed the release of ticagrelor for antiplatelet therapy.Animal studies indicated that PEG-LCN-uPA exhibited effective thrombolysis in both mice tail thrombus models and carotid arterial thrombosis model without obvious safety issues.The decrease of sCD40L level indicated the effective reduced activation of platelet,which benefits for long-term antithrombus therapy.With these abilities,PEG-LCN-uPA presented its potential as a feasible strategy for thrombosis-related diseases treatment.
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