Construction And Evaluation Of Glutathione-responsive Nanodrug Delivery System Self-assembled By Curcumin Dimer

Curcumin(CUR)is a natural anticancer drug with minor side effects.However,due to its poor water solubility and stability,short half-life,and undesired drug absorption,its biological activity is unsatisfactory,which affects its further clinical application.In order to overcome the above shortcomings,nanodrugs have been widely used in research for CUR.However,the introduction of additional carrier materials makes low drug loading,and there may be potential toxicity and in vivo excretion,metabolism and degradation problems.In view of this,CUR dimer(CUR-S-CUR prodrug)was synthesized by glutathione-responsive single sulfur bond based on esterification reaction and nanodrug delivery system based on CUR-S-CUR prodrug was self-assembled by supramolecular technology.In vivo and in vitro properties were evaluated,and the main contents were as follows:(1)The glutathione-responsive CUR-S-CUR dimer was synthesized from 2,2'-thiodiacetic acid and CUR by esterification,and the successful synthesis of CUR-S-CUR dimer was characterized by fourier transform infrared spectroscopy(FTIR),X-ray diffraction(XRD),nuclear magnetic resonance(NMR),ultraviolet-visible spectrophotometer(UV-Vis),and mass spectrometer(MS).(2)CUR-S-CUR dimer could self-assemble to form CUR-S-CUR@PEG nanoparticles(NPs)by nano-precipitation method and DSPE-PEG modification.The characterization results showed that CUR-S-CUR@PEG NPs were spherical,particle size was about to 80 nm,and zeta potential was about-25 mV.The further investigation indicated that the release of CUR from CUR-S-CUR@PEG NPs could be triggered by GSH.(3)In order to evaluate the anti-tumor ability of CUR-S-CUR@PEG NPs,in vitro cell uptake and toxicity,in vivo fluorescence,and in vivo anti-tumor experiments in mice were further studied.The experimental results showed that CUR-S-CUR@PEG NPs could be effectively uptaked by cells and transport to the perinuclear region and gradually enter the nucleus,and CUR-S-CUR@PEG NPs exhibit the same inhibitory effect as free CUR.In vivo fluorescence studies showed that CUR-S-CUR@PEG NPs could accumulate into tumor tissues through passive targeting mediated by EPR effect,reduce the clearance rate of CUR in vivo,enhance its half-life,and reduce the accumulation of drugs in normal tissues to reduce drug side effects.The results of anti-tumor experiments showed that CUR-S-CUR@PEG NPs could rapidly release CUR and exert anti-tumor effect under the trigger of GSH overexpressed by tumor cells after accumulation at tumor sites through EPR effect,and no obvious toxic and side effects were found during investigation.