Redox Responsive Mesoporous Silica Nanoparticles Delivery System Of Arsenic Trioxide Against Hepatic Carcinoma

Objective The redox responsive nanodrug delivery system of MSN-SS-PEG@As₂O₃was constructed based on mesoporous silica nanoparticle（MSN）,which both modificated by redox-sensitive disulfide bonds and non-toxic,non-immunogenic polyglycols（PEG）could control release of arsenic trioxide（As₂O₃）.To solve the problem of As₂O₃ treatment window stenosis,rapid elimination in vivo,poor specific distribution and others,in order to achieve responsive release of As₂O₃ drugs in the tumor site,thereby improving the efficacy of liver cancer.Methods Redox response drug delivery system（MSN-SS-PEG）was synthesized by mesoporoussilicananoparticles,（3-mercaptopropyl）trimethoxysilane,2-（2-pyridyldiyl）ethylamine hydrochloride,Methoxy-terminated polyethylene glycol（MPEG2000-NHS）.The particle size and zate potential were measured by a Malvern particle size analyzer,and the success of each modification was verified by infrared spectroscopy.The physical and chemical properties of the nanocarriers were investigated by small angle powder diffractometer and nitrogen adsorption desorption instrument.The encapsulation efficiency（EE%）and drug loading efficiency（DL%）were determined by inductively coupled plasma emission spectrum（ICP）.DL%was also investigated by Thermogravimetric analysis（TGA）.The dialysis bag method was used to investigate the in vitro release characteristics of nanocomposites under different conditions.An MTT assay was used to evaluate the cytotoxicity of drug-free carriers（MSN,MSN-SS-NH₂,MSN-SS-PEG）and As₂O₃ formulations on Hep G2 and LO2 cells.The uptake of FITC-labeled delivery system in human hepatocellular carcinoma cells（Hep G2）were investigated by laser confocal microscopy.In this study,it established Hep G2 hepatocellular carcinoma model nude mice and the effect of antitumor activity in vivo were evaluated by the body weight,tumor growth,the survival time of the tumor-bearing mice,and the H&E staining by tumor tissue.Results The particles size of MSN-SS-PEG was（159.6±3.10）nm,and the zeta potentials of MSN,MSN-SS-NH₂,MSN-SS-PEG were（-13.4±0.87）m V,（+31.63±0.90）m V,（+27.7±5.6）m V respectively,and MSN-SS-PEG eventually stay positive.Transmission electron microscopy showed that the MSN,MSN-SS-NH₂,and MSN-SS-PEG were round or near round.The drug loading of MSN-SS-PEG@As₂O₃were 4.38%measured by ICP.The release of MSN-SS-PEG@As₂O₃ was 55.16%,69.49%,81.00%in the release medium of glutathione（GSH=10 m M）p H of 7.4,6.5,and 5.0 at 24 h,respectively.MSN-SS-PEG@As₂O₃ at a p H of 5.0,the release amount of the glutathione releasing medium was 25.28%.The in vitro release results indicated that MSN-SS-PEG@As₂O₃ had a redox/p H dual sensitivity response.In vitro cell experiments showed that Hep G2 cells were more sensitive to the toxicity of the carrier than LO2 cells.With the increase of the concentration,the survival rate of MSN-SS-PEG was greater than that of MSN-SS-NH₂,indicating that the PEG modification further reduces the cytotoxicity of the carrier and improves the biocompatibility.In vitro anti-tumor experiments showed that the anti-tumor effect of MSN-SS-PEG@As₂O₃ was significantly higher than that of other preparations.The uptake of each carrier with FITC fluorescence in laser confocal experiments showed that the uptake of MSN-SS-PEG and MSN-SS-NH₂ by Hep G2 cells were significantly higher than that of MSN,and it may be related to the increase in positive charge increasings the uptake capacity.The in vivo pharmacodynamics results showed that the mean tumor volume of the MSN-SS-PEG@As₂O₃ group was significantly lower than that of the MSN-SS-NH₂@As₂O₃ group（p<0.05）and saline group（p<0.01）,and the median survival time of the MSN-SS-PEG@As₂O₃ group was significantly higher than that of the normal saline（p<0.01）,The As₂O₃ drug（p<0.01）,MSN-SS-NH₂@As₂O₃ group（p<0.05）,the median survival time has been greatly extended,indicating that the MSN-SS-PEG@As₂O₃ group has a significant anti-tumor effect.Conclusions The MSN-SS-PEG@As₂O₃ prepared in this paper had a round and uniform particle size,and the modified silica delivery system had a better cell uptake effect than the silica delivery system.The responsive release of MSN-SS-PEG@As₂O₃ in the special tumor environment increased the accumulation of drugs in the tumor site,prolonged the survival time of the nude mice and enhanced anti-hepatocarcinoma effect in vivo.