| Curcumin(CCM)is one of the main functional components of Chinese traditional Chinese medicine turmeric.Modern medical studies have shown that curcumin has a wide range of pharmacological activities,and it has obvious effect on the prevention and treatment of many diseases.However,curcumin is almost insoluble in water,and curcumin has less absorption in the human body,rapid metabolism and low bioavailability,these defects greatly limit its clinical application.Therefore,in order to improve the stability of curcumin in human body and enhance its biological activity,it is necessary to modify the structure of curcumin or prepare curcumin analogues.In this paper,a series of curcumin derivatives were synthesized by chemical modification of the structure of curcumin,and the derivatives with good activity were selected by in vitro activity screening.then the compound and curcumin matrix were encapsulated in human serum albumin(HSA)and formed nanoparticles by albumin nano-binding technology.Finally,the prepared nanoparticles were characterized and evaluated.In the aspect of chemical structure modification of curcumin,based on the previous synthetic experience of the research group,curcumin derivatives substituted by isopentenyl groups were designed and synthesized using vanillin as the starting material.After the optimization of three routes,a synthetic route with shorter route and higher yield was finally determined.On the basis of this route,10 target curcumin derivatives were synthesized.Among them,8 compounds are new compounds which have not been reported in the literature,and their structures have been confirmed by 1H NMR,13C NMR and high resolution mass spectrometry.The results of bioactivity test in vitro showed that the antioxidant effects of the 10 compounds were particularly significant,among which compound 2,compound 4 and compound 5 had the best antioxidant activity.therefore,on this basis,compound 2 was selected as the representative compound for the next stage of study.The nanoparticles containing curcumin CCM and compound 2 were successfully prepared by albumin nano-binding technology(NP-CCM and NP-2),HPLC showed that the entrapment efficiency of the two nanoparticles was close to 100%,and the drug loading was 6.45%and 7.39%,respectively.The dynamic light scattering(DLS)showed that the particle sizes of the two nanoparticles were 109.2nm and 110.9 nm,respectively,and the Zeta potentials were-15.3 mv and-15.1 mv,respectively.These negative charges make the nanoparticles not easy to aggregate in aqueous solution and have good dispersion.NP-2 has good stability under physiological conditions,and the drug content does not change within 48 hours in PBS buffer solution(pH=7.4)at 37℃.The drug release experiment in vitro simulates the release of two kinds of nanoparticles in tumor environment at the concentration of high glutathione(GSH).The results show that the two nanoparticles show glutathione responsive release,but the nanoparticles NP-2 has a sustained release effect.In the experiment of inhibiting tumor cell growth by MTT method,three kinds of cancer cells,human leukemia cell line K562,human liver cancer cell line HepG2 and colon cancer cell line HCT-116 were tested.The results showed that the cytotoxicity of nanoparticles NP-2 to these three kinds of tumor cells was significantly higher than that of compound 2 itself.Antioxidant experiments in vitro showed that NP-2 nanoparticles had stronger cytoprotective effect than compound 2,and could completely reverse the oxidative damage of PC-12 cells induced by hydrogen peroxide,which was speculated to be related to the improvement of stability and physical and chemical properties of the compound after binding to albumin.To sum up,the NP-2 nanoparticles modified by isopentenyl group and combined with albumin improved the physical and chemical properties of curcumin and enhanced the biological activity of curcumin,which provided a new idea for the clinical application of curcumin. |
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