Preparation And Performance Of Environmentally Responsive Gated Mesoporous Silica Drug Carriers

Intelligent drug carriers have shown broad prospects in clinical medicine,including the delivery of guest molecules,tracking imaging and synergistic therapy.In this paper,mesoporous silica was modified with benzimidazole and ferrocene organic molecules.Multi-arm star polymer?-CD-PNIPAM was prepared via using cyclodextrin as core and poly-N-isopropylacrylamide as arm.A series of environmentally responsive intelligent gated nanocarriers were designed through hydrophilic-hydrophobic inclusions between functionalized mesoporous silica and?-CD-PNIPAM.The drug-carriers were analyzed by TEM,TGA,elemental analysis and other methods.In addition,the environmental responsiveness and drug release behaviors of nanoparticles were investigated by changing the temperature,acid,concentration of oxidant and glutathione?GSH?.The benzimidazole?BM?was grafted onto mesoporous silica nanoparticles?MSN?via?3-chloropropyl?trimethoxysilane?CPTOS?.N-isopropylacrylamide?NIPAM?was modified with?-cyclodextrin??-CD?by atom transfer radical polymerization?ATRP?to prepare temperature-sensitive star polymers??-CD-PNIPAM?.The model drug DOX was loaded into MSN channels and then?-CD-PNIPAM was complexed with functionalized mesoporous silica to form an intelligent"valve"for controlling drug release.The composite nanoparticles showed ordered mesoporous structure with100-150 nm diameter and 2-3 nm mesopore size.When the dosage of DOX was100%,the DLC%and EE%were 40.51%and 85.11%,respectively.The release of drugs can be controlled by external environmental stimuli in vitro release experiments,fot instance,acid and temperature.Higher acidity and temperature,faster release of DOX from nanoparticles and cumulative drug release reached 95%at pH=2.0 within8 hours.About 60%of DOX was released into the environment at 25°C within 10hours,however,the cumulative release can reach 100%under 42°C.So,the behavior of drug release exhibited temperature and pH sensitivity.MSN-Fc modified ferrocene carboxylate provided redox sites that formed oxidative and temperature-responsive nanoparticles with regular spherical structures via capping?-CD-PNIPAM.The cytotoxicity of nanoparticles against HeLa cells was investigated by MTT assay.The cell viabilities for blank nanoparticles remained more than 96%even at the concentration up to 0.2 mg/m L,suggesting nanoparticles were biocompatible.Nanocarriers have high drug loading capacity for IND,NAP,DS and DOX,especially for DOX.When dosage of DOX was increased to 80%,the DLC%and EE%of nanoparticles were 38.00%and 71.04%,respectively.The release of drugs can be triggered by adjusting the concentration of H₂O₂ and temperature.When the concentration of H₂O₂ increased from 0.5%to 1.0%,the cumulative release of DOX within 10 hours increased from 37%to 52%.For temperature,the cumulative release of DOX increased from 70%to 93%when temperature rised from 25°C to42°C within 10 hours.Drug release kinetics indicated that the release of guest molecules was more consistent with Korsmeyer-Peppas model and non-Fickian diffusion mechanism in the presence of oxidant.For temperature stimulus,the release process was satisfied with both Bhaskar and Korsmeyer-Peppas models.Disulfide bond and Fc-modified MSN?MSN-SS-Fc?was successfully complexed with?-CD-PNIPAM through host-guest interaction to prepare GSH/H₂O₂/temperature multiple stimuli responsive drug carriers.Nanoparticles exhibited regular spherical structure with uniform particle size of 100-200 nm.It can be indicated from UV-visible absorption spectrum and release curve of carriers that?-CD-PNIPAM can significantly inhibit drug release.Inhibition of?-CD was disappeared because of Fc protonation and then loaded drugs were released under acid and H₂O₂.The release of drugs can be triggered by GSH,H₂O₂ and temperature.Cumulative release amount of DOX and NAP both reached 100%within 48 hours in the presence of GSH?10 mM?.In addition,the release of drugs from nanocarriers can be controlled by temperature.The cumulative release of DOX at 42°C was significantly greater than 25°C within34 hours.