Investigation On The Preparation Of Functionalized Mesoporous SiO₂ Support Materials And Its Performance Of Loaded Antitumor Drugs

Mesoporous silica materials has become a good carrier for various guest molecules and thus is widely applied to load antitumor drugs for its unique physicochemical properties,such as highly ordered mesopores,large specific surface area and pore volume,easy surface functional modification,good biocompatibility,diverse morphology and good adsorption capacity.However,there are still some problems need to be improved in the research,such as how to increase the drug loading;how to achieve“zero early release”before reaching the target sites;how to maintain a stable drug release for a long time while targeting;how to achieve simultaneous loading of drugs with different molecular weights or different properties and the synergistic effect between different drugs that co-loaded.Focusing on the above problems,this study prepared the functionalized mesoporous SiO₂ support materials to load antitumor drugs.In this study,a series of mesoporous SiO₂ support materials were prepared.The crystal phase and structure information were obtained by X-ray diffraction to determine the type of prepared materials.The morphology was observed by scanning and transmission electron microscopy.The N₂ adsorption-desorption was used to detect the porous properties,including the specific surface area,pore size distribution and pore volume.The cell uptake characteristics were evaluated by laser scanning confocal microscope.The in vitro cytotoxicity of materials was examined by standard MTT assays.And the in vitro release experiments were conducted to investigate the feasibility of materials as drug carriers in stimulating the controlled release behavior of responsive drugs.The specific research contents and results are as follows:?1?A series of mesoporous silica nanoparticles?MSNs?with different particle sizes were prepared by controlling the reaction time,temperature and the mass ratio of raw materials using sol-gel method.The effects of six different particle size MSNs on cytotoxicity and cellular uptake to human cervical cancer cells?Hela?and human non-small cell lung cancer cells?A549?were studied.The in vitro cell experiments showed that the prepared MSNs entered the cell through the lysosome and localized in the cytoplasm;they were less cytotoxic to Hela cells and A549 cells except the largest size particles,among which the 130 nm MSNs is minimal.?2?The modified silane coupling agent was used to modify mesoporous silica nanoparticles,and a pH-responsive drug carrier system based on amino functionalized MSNs was constructed to achieve high-efficiency loading of the model drug ibuprofen?IBU?.The carrier rate of 36 h achieved 49.47%.The experiments of in vitro drug release showed that the synthesized material was pH sensitive to the release of the small molecule drug ibuprofen.At high pH?pH=7.45?,the IBU drug loaded in nanoparticles was slowly released within 50 h;at low pH?pH=4.5?,only part of the IBU was slowly released within 25 h while most of the IBU was confined within the mesopores effectively and released completely after 25 h.In vitro cytotoxicity test showed that the drug-loading system has good biocompatibility.?3?The targeted multi-functional mesoporous silica nanoparticle drug carrier?MSN-130-COOH-Tet-HBP-FA?was prepared by modifying MSNs with carboxyl and making use of the pH responsiveness of hyperbranched polymer?HBP?to achieve controlled release of the model drug of tetrandrine?Tet?,followed the introduction of targeting ligand compounds of folic acid?FA?.It showed that the loading rate of the model drug tetrandrine?Tet?was 26.86%after the carboxyl groups modification.The hyperbranched polymer can be used as a mesoporous plugging material to block the drug molecules in the mesopores effectively and the encapsulated MSN-130-COOH-Tet-HBP-FA can be achieved“zero early release”within 20 h under normal cellular physiological environment?pH=7.4?.Due to a large number of amino groups of HBP,it is beneficial to achieve pH responsiveness and introduce other functional groups molecules,such as targeting molecules.In vitro cell culture experiments showed that this nano drug-loading system has good biocompatibility and enters Hela cells and A549 cells through the lysosome.And the targeting of folate receptor-mediated allows the drug to be stable in the cytoplasm for a long time?24 h?and exert its efficacy continuously?the cumulative release rate within 72 h was only 30%?.In vitro drug release experiments showed that the drug carrier system was pH responsive,which inhibit drug release in a neutral environment while release drug molecules rapidly in an acidic environment.?4?The spherical mesoporous silica particles with double mesoporous structures?the poro size distribution about 2-4 nm and 4-12 nm,respectively?were prepared using different structure directing agents and adding the pore-expanding agent by one-pot method.The nanoparticles were functionalized with amino and carboxy groups and loaded the macromolecular protein model bovine serum albumin?BSA?and the small molecule drug model doxorubicin?DOX?or cisplatin?DDP?simultaneously.The drug carrier systems with targeting function and pH stimuli responsiveness?DMSN@NH₂@COOH@DDP@BSA andDMSN@NH₂@COOH@DOX@BSA?were conducted by grafting NH-?-cyclodextrin to block the mesopores and introducing folic acid?FA?to achieve targeted functionalization.The results of the drug-loaded experiments showed that the amino and carboxy functionalized nanoparticles performed a high loading rate for the drugs of DOX,DDP and BSA,especially BSA,which is not affected by the loading of small molecule drugs with a high loading rate of 33%.In vitro drug release experiments showed that the drug carrier system was pH responsive and is capable for protecting protein molecules from degradation before reaching the target sites.Meanwhile,the drug-loading system was good biocompatibility and the cytotoxicity of DDP was reduced significantly after being loaded into the drug-loading system.Both in vitro cytotoxicity and cellular uptake experiments suggested a mediated role of folate receptors.?5?The coral-like mesoporous silica particles?CMS?with large pore size were prepared using triblock polymer PEG-b-PEO-b-PEG and hydrothermal method.It was modified with carboxyl groups to obtain carboxyl functionalized support material?CMS-?NH?₃-COOH?.Two drugs?gefitinib and DOX?were co-loaded to construct a pH responsive and gefitinib/DOX synergistic drug delivery vehicle system.The drug-loaded experiments showed that the system had a high loading rate for both drugs?GB and DOX were 47.36%and 26.74%,respectively?.In vitro drug release and cytotoxicity experiments indicated that the system was pH responsive and low cytotoxicity especially when these two drugs loading into the carrier,the cytotoxicity reduced significantly.And the carrier system?CMS-?NH?₃-COOH@GB@DOX?loaded with two drugs had a significant synergy to the proliferation and apoptosis of A549 cells.