Research On FRET-based Redox-responsive Mesoporous Silica Nanoparticles For Drug Delivery System

The release of drugs at specific target sites can maximize the efficacy of malignancies and reduce the drug toxicity to healthy cells and tissues.So the development of the targeted drug delivery systems(DDS)have made considerable progress in recent years.However,these DDS still have some shortcomings,mainly involving the lack of a platform which can real-time monitor the anti-cancer drugs,especially non-fluorescent drug release.Therefore,it is of great significance to integrate controlled release with real-time monitoring in the same DDS.To achieve this goal,we constructed a novel multifunctional DDS which can target the CD44 receptor,response to reductive agent to realize the controlled release and the real-time monitoring of drug release processes based on fluorescence resonance energy transfer(FRET).In this paper,thiol-functional colloidal mesoporous silica nanoparticles(CMS-SH)were prepared by co-condensation method with triethanolamine instead of sodium hydroxide and ammonia.Then,Znq-CMS as a drug storage tank and FRET energy donor was prepared by the introduction of 8-hydroxyquinoline zinc which can interact with mercapto groups to form complex compound through in situ formation method.Following the mesoporous silica nanoparticles containing disulfide bond and terminated with amino group(Znq-CMS-SS-NH2)was obtained by carboxylation and cystamine modification on the surface.Finally,the fluorescent polymer RhB-EA-HA which simultaneously serve as a plugging agent,target and FRET energy receptor,was grafted onto the surface of Znq-CMS-SS-NH2 by amidation reaction to successfully obtain the FRET-based redox response mesoporous silica nano-drug delivery system(FRET-CMS).In addition,we used 6-mercaptopurine(6-MP)as the model drug and FRET-CMS as the carrier to investigate the in vitro drug loading and redox response drug release properties,and the change of fluorescence signal of FRET-CMS in glutathione were also investigated.In this paper,a variety of instruments were used to characterize the experimental samples.The results are as follows:(1)CMS-SH and Znq-CMS show a regular spherical morphology and have obvious worm-like channels.The size were relatively uniform and the particle size were about 85 nm.It can observe the typical ? type mesoporous structure,high specific surface area and large pore volume.And they also have good stability.Znq-CMS has a strong green fluorescence,and its fluorescence in a certain time and pH range is relatively stable.(2)Mesoporous silica nanoparticles containing disulfide bond and terminated with amino group(Znq-CMS-SS-NH2)was prepared by post-grafting and amidation reaction.The carboxyl groups modification was identified by FT-IR and the cystamine functionalization was characterized by Zeta potentials.It indicated that the carboxyl groups and cystamine had been successfully graft on the surface of the fluorescent mesoporous silica.And the fluorescence emission wavelength of the functionalizedmesoporous silica was blue shifted 15 nm.(3)FRET-CMS showed good stability in aqueous solution.TEM presented that both the nanoparticles were spherical morphology before and after the modification of the polymer,and the size of the FRET-CMS was uniform.But the the mesoporous of FRET-CMS become blurred due to the block of polymer chain.N2adsorption-desorption analysis showed that FRET-CMS was a typical type ?mesoporous structure,but the specific surface area,pore volume and pore size of FRET-CMS was smaller than that of Znq-CMS which before polymer modification due to the wrapped polymer.In addition,at the excitation wavelength of 380 nm,FRET-CMS presented two fluorescence emission peaks due to the intact energy donor-receptor pair which induced FRET switch open.When a certain concentration of glutathione(GSH)was added,FRET switch closed and the red fluorescence at 571 nm is gradually reduced company with the green fluorescence at 495 nm is gradually enhanced.It demonstrated that GSH can effectively control the FRET.6-MP was effectively encapsulated in the mesoporous channels of FRET-CMS with the drug loading rate and entrapment efficiency were 8.39% and 91.55%,respectively.The6-MP@FRET-CMS was not released within 24 hours in the absence of GSH.When adding a certain concentration of GSH,the 6-MP was released from the mesoporous channel and exhibited a redox responsive drug release curve.In summary,FRET-based redox responsive mesoporous silica nano-drug loading system provides a good technology platform for the targeted delivery,controlled release and real-time monitoring of drug release.It is a promising nano-carrier for drug delivery.