Construction And Properties Of Dual Responsive Smart Drug Carriers Based On Hollow Mesoporous Silica

The design of intelligent drug delivery systems can effectively improve the encapsulation efficiency of antitumor drugs,reduce the toxicity to healthy tissues and organs,and improve the therapeutic effect.In this paper,two smart drug delivery systems based on hollow mesoporous silica nanoparticles（HMSNs）were designed and their encapsulation,release and toxicity to tumor cells of doxorubicin（DOX）were investigated.The hydrophilic polymer polyethylene glycol monomethyl ether（MPEG）can improve the dispersibility of nanoparticles and avoid accumulation in the body or phagocytosis by immune proteins.The polymer segment of the thermosensitive polymer poly-N-isopropylacrylamide（PNIPAM）is in an extended state at room temperature（25°C）,allowing drugs to enter,and the segment collapses at body temperature（37°C）,blocking the HMSNs mediator.holes to prevent premature drug leakage.Ce O₂is stable in conventional environment and can be used as a blocking agent for HMSNs.It is dissolved into Ce³⁺in acidic and GSH environments,and Ce O₂has a certain inhibitory effect on tumor cells.The pH-sensitive connection between HMSNs and the shell can realize intelligent drug release.The two smart drug carriers designed in this paper have dual responsiveness to temperature/pH and redox/pH,respectively.The specific research contents are as follows:（1）mercaptoethanol is used as chain transfer agent,and azobisisobutyronitrile（AIBN）is used as initiator to initiate free radical polymerization of monomer N-isopropylacrylamide（NIPAM）toobtainhydroxyl-terminated poly-N-isopropylacrylamide（PNIPAM-OH）,which was further modified by p-aldehyde benzoic acid to obtain PNIPAM-CHO,and MPEG-CHO was obtained by the same method.HMSNs was synthesized by selective etching,and the two polymers were grafted on the surface of HMSNs by Schiff base reaction to obtain a temperature/pH dual-responsive mixed-shell HMSNs（Mixed-HMSNs）.Increasing the proportion of the two polymers can change the dispersion and encapsulation efficiency of nanoparticles,respectively.The drug release rate of nanoparticles in the acidic environment（pH=5.0）is much higher than that in the neutral environment（pH=7.4）.The release rate at 25°C was higher than at 37°C.The uptake experiment shows that the nanoparticles can enter the interior of the cell,and the MTT experiment proves that the nanoparticles have no obvious toxicity to normal cells,but have targeting and slow-release effects on tumor cells.（2）By adjusting the ratio of ammonia water and solvent,the selective etching method was improved to synthesize HMSNs with a diameter of less than 150 nm,and the small size of HMSNs is more suitable as a drug carrier.Using cerium nitrate hexahydrate(Ce（NO₃）₃·6H₂O as raw material to synthesize cerium dioxide（Ce O₂）nanoparticles by hydrolysis precipitation method.MPEG grafting,DOX loading and Ce O₂capping were performed on HMSNs in turn to obtain pH/GSH dual-response drug release system（DOX-HMSNs-PEG/Ce O₂）.Its structure was characterized,and the encapsulation and release properties of nanoparticles for DOX,as well as the inhibitory effect on tumor cells were studied.The results showed that the drug release rate in the acidic environment（pH=5.0）is higher than that in the normal tissue environment（pH=7.4）,and the drug release increases with the increase of GSH content.Uptake experiments show that nanoparticles can enter tumor cells,MTT experiments show that drug-loaded nanoparticles have no obvious toxicity to normal cells,while it is toxic to tumor cells,and has certain targeting and sustained-release effects;unloaded HMSNs-PEG/Ce O₂has a certain inhibitory effect on tumor cells,which can enhance the therapeutic effect.