Abstract
In this study, covalent conjugation of thrombolytic drug urokinase to water-soluble magnetic nanoparticles (NPs) is proposed to enhance the efficiency of thrombolysis. Hydrophobic NPs of oleic acid (OA)-coated Fe3O4 are first synthesized and then surface-modified with the amphipathic copolymer poly(maleic anhydride-alt-1-octadecylene) (PMAO) to form water-soluble NPs of PMAO-OA-Fe3O4 with monodispersed sizes. PMAO-OA-Fe3O4 NPs display a good water-based stability without aggregation at near neutral pH and show good magnetic separation characteristics. The thrombolytic drug urokinase is then covalently linked with the former product through dehydration condensation reaction between the amino and carboxyl produced by dehydration of the anhydride under N-Ethyl-N′-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). Transmission electron microscope (TEM) images and dynamic light scattering (DLS) results show that the urokinase@PMAO-OA-Fe3O4 NPs are uniformly dispersed in water. The in vitro thrombolytic effect based on the manipulation of magnetic coupling, combined with static and alternating current (AC) magnetic fields, in a mimic blood-vascular system was studied. Drug release test shows that AC magnetic field can be used as switch and accelerator for NPs to release drugs. In addition, thrombolytic efficiency is nearly four times that of pure urokinase. This indicates that the coupling magnetic field may be a promising method to improve thrombolytic effect of the prepared magnetic carrier drug conjugates.
Highlights
Thrombosis is a serious disease that threatens the lives of people all over the world [1]. research on rapid thrombolysis has progressed in recent decades [2,3], the treatment of possible hemorrhage by using large dosage of thrombolytic drugs continues to greatly restrict the improvement of medical care [4,5]
The regent kit containing the solution of urokinase@poly(maleic anhydride-alt-1-octadecylene) (PMAO)-oleic acid (OA)-Fe3 O4 NPs (756 μg urokinase coated on 1 mg PMAO-OA-Fe3 O4 NPs) was placed in the working area of the magnetic control system, and the alternating magnetic fields of different frequencies generated by the cores on the x-axis and z-axis were applied to the regent kit for several minutes
The drug carrier of water-soluble PMAO-OA-Fe3 O4 particle was first prepared into nano-scale monodisperse, and successfully covalently bound with urokinase for thrombolysis
Summary
Research on rapid thrombolysis has progressed in recent decades [2,3], the treatment of possible hemorrhage by using large dosage of thrombolytic drugs (e.g., urokinase and streptokinase) continues to greatly restrict the improvement of medical care [4,5]. Magnetic nanoparticles (NPs) have gained significant attentions for their applications in magnetic resonance image (MRI) [9,10], cell separation [11,12], and gene therapy [13]. Magnetic NPs have been used as drug carriers for targeting therapies, such as cancer [14,15], cardiovascular diseases [16], and infectious diseases [17]
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