| The drugs reached the targeted sites will take some time after the administration of targeted drug delivery system.In recent years,it has become a hot issue of pharmaceutical research that how to reduce the premature release of targeted drug delivery system before it reached the targeted sites.And the drug would release intensively and fast according to the special physiological conditions to improve the therapeutic efficacy and reduce side e ffects of drugs after the arrival of the tar get site.In order to construct stimuli-responsive drug delivery systems(DDS)in which the drugs were covalently binding or physically entrapped in the mesopores of silica,two kinds of mesoporous silica were prepared.Firstly,inners and outer surface of carrier were modified with thiol to covalently load the drug with a thiolated group.The cetyl trimethyl ammonium chloride(CTAC)was used as a template and(3-mercaptopropyl)trimethoxysilane(MPTMS)was used as a mercapto reagent to prepare the colloidal mesoporous silica(CMS)carriers with different modified thiol amounts by the co-condensation method.The prepared nanoparticles were homogeneous spheres with the average particle diameters of ca.60-80 nm.The results of X-ray photoelectron spectroscopy(XPS)and specific surface area and pore size analysis indicated that with the increasing addition volume of MPTMS,the diameter of the carriers slightly increased and the mercapto group content were increased proportionally on the inner and outer surfaces,but the pore diameter of CMS gradually reduced.In addition,the mesoporous silica nanoparticles(MSN)with two-dimensional arrangement of mesopores was prepared by the using of cetyl trimethyl ammonium bromide(CTAB)as a template.The BET specific surface area and pore size of MSN-SH was 1268 m2·g-1 and 2.8 nm,respectively.The thiol-functionalized MSN(MSN-SH)was prepared by the post-modification method.The pore size of MSN-SH was 2.7 nm and it did not change significantly after the thiol modification The result of XPS indicated that the content of S element of MSN-SH was 4.81%,indicating that the mercapto groups were modified on the surface of MSN-SH.A redox-responsive drug delivery system(CMS-SS-MP/PEG)based on colloidal mesoporous silica(CMS)has been developed in order to reduce the premature release of drugs,in which 6-MP and mPEG was covalently conjugated to interiors and exteriors of mesoporous silica by cleavable disulfide bonds.The drug loading efficiencies before and after the grafting of mPEG was evaluated,and it was found that the carrier had the highest drug loading efficiency up to 4.07%with the addition of 0.5 mL MPTMS.In vitro drug release results showed that no premature release was observed from CMS-SS-MP/oHA in the absence of GSH.However,in the presence of 3 mmol·L-1 GSH,CMS-SS-MP/oHA with drug conjugated to CMS by disulfide bonds exhibited redox-responsive release,and the cumulative release reached more than 70%within 2 h.In addition,by comparing the cumulative release profiles of CMS-SS-MP/mPEG with their counterparts without the grafting of PEG,it was found that mPEG chains did not hinder the drug release.The properties of the carriers were evaluated before and after the grafting of mPEG The experimental results show that the hemolysis percentage of the sample after the modification of PEG was significantly decreased from 66.5%to 1%at the concentration of 1500 ?g·mL-1.The protein adsorption amount of CMS-SS-PEG-2 decreased by 80%compared with CMS-2SH,and particle size did not change significantly after the drying,indicating that the good biocompatibility of mPEG modified carrier.Based on the previous studies,the CMS-2SH was used as a carrier and oHA used as a targeting ligand to prepare the oHA modified redox-responsive targeted drug delivery system(CMS-SS-MP/oHA)to endow the targeting feature of the DDS.In vitro release results showed that the prepared DDS exhibited highly redox-responsive release characteristics.The oHA grafted to the surface of carriers could increase the biocompatibility and dispersibility of CMS under physiological conditions.The targeting tests show that the mean fluorescence intensity(MFI)of FITC labeled CMS-SS-oHA was 1.8 times in CD44 receptor overexpressed HCT-116 cells compared with the MFI in NIH-3T3 cells,indicating that the oHA could increase the uptake performance of CMS-SS-oHA in HCT-116 cells via CD44 receptor-mediated endocytosis.MTT test showed that CMS-SS-MP/oHA could increase the cytotoxicity in HCT-116 cells.To increase the applied range of stimuli-responsive silica and endow the new function of carrier,the redox and enzyme dual-stimuli responsive delivery system(MSN-SS-HA)based on mesoporous silica nanoparticles(MSN)for targeted drug delivery has been developed,in which hyaluronic acid(HA)was conjugated on the surface of silica by cleavable disulfide bonds.Doxorubicin(DOX)was used as a model drug.When MSN-SH was used as the initial drug carrier,the DDS had the largest drug loading was up to 10.6%.In vitro release results showed that the prepared MSN-SS-HA/DOX exhibited highly redox and enzyme dual-stimuli responsive release.The targeting tests show that the MFI of FITC labeled MSN-SS-HA was 3 times in HCT-116 cells compared with that in NIH-3T3 cells,indicating that the HA could increase the uptake performance of MSN-SS-HA in HCT-116 cells via CD44 receptor-mediated endocytosis.MTT test showed that MSN-SS-HA/DOX could increase the cytotoxicity in HCT-116 cells compared with that in NIH-3T3 cells.In vivo anti-tumor efficacy and biodistribution results showed that MSN-SS-HA/DOX with higher tumor tissue distribution can significantly increase the tumor suppression effect,and the tumor inhibition rate was 78.2%.The body weight of nude mice did not change significantly after the administration of MSN-SS-HA/DOX,while the body weight showed significant decline after the administration of DOX solution,indicating that MSN-SS-HA/DOX could significantly reduce the toxicity of DOX and,to some extent,increase the safety of DDS. |
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