PEGylation of lumbrokinase improves pharmacokinetic profile and enhances anti-thrombotic effect in a rat carotid artery thrombosis model

Abstract

The present study aimed to prepare injectable Lumbrokinase (LK) with long circulation time in addition to enhanced anti-thrombotic efficacy. Following preparation, the pharmacokinetic and anti-thrombotic effect of the drug in a rat carotid artery thrombosis model was evaluated. The drug was prepared by conjugation of LK with mPEG-SC20000 as previou sly reported. The pharmacok inetics of them PE G - SC20000-LK were then examined and the anti-thrombotic activity in an artery-vein bypass thrombosis rat model was evaluated. Finally, the parameters of fibrinolysis including thromboxane B2, prostaglandin F1α, tissue plasminogen activator and plasminogen activator inhibitor-1 were compared between native LK and mPEG-SC20000-LK in a FeCl3-induced carotid artery thrombosis rat model. mPEG-SC20000-LK was successfully prepared by PEGylation of LK with mPEG20000-SC in optimal conditions. Pharmacokinetic analysis demonstrated that the biological half-life of the mPEG20000-SC-LK increased by 2.2-fold compared with native LK. In vivo anti-thrombotic analysis indicated that mPEG20000-SC-LK exhibited a greater anti-thrombotic effect in artery-vein bypass thrombosis and FeCl3-induced carotid artery thrombosis models compared with native LK. In conclusion, injectable PEGylated LK with prolonged half-life and enhanced anti-thrombotic effect is a potential anti-thrombotic agent for long-acting treatment of the thrombus diseases.