Construction Of Functionalized Mesoporous Silica Nanocomposite Drug Carrier And Its Application In Cancer Therapy

The establishment and development of nano-drug carriers provide an effective way for cancer treatment.Mesoporous silica nanoparticles(MSN)have become one of the important drug carriers due to their special mesoporous structure,prominent stability,biocompatibility,and high drug loading capacity.Surface modification of MSN with drug molecules,targeting groups or nanoparticles to build functionalized MSN nanocomplexes can not only prevent premature release of drugs,treat tumors accurately and effectively,but also achieve synergistic multi-therapy.It has potential application value in the field of cancer therapy.In this thesis,MSN were used as a carrier,and three kinds of functionalized MSN nanomedicine carriers were prepared by redox reaction,amidation reaction and oxidizing self-polymerization with guest materials or drug molecules,which had stimuli-responsive drug release performance,and provide synergistic multi-therapy.The concrete contents are as follows:Chapter 1: We briefly described the definition,structure,properties,types and targeted delivery of nano-drug carriers,the preparation and functionalization of MSN,and the types of MSN-based stimulus responses,and further reviewed the research progress of MSN in cancer treatment.Chapter 2: The manganese dioxide shell(Mn O2)was coated on the surface of the thiolated MSN by redox reaction,and polyallylamine hydrochloride(PAH)was further electrostatically adsorbed on the surface.The nanocomplex MSN@Mn O2-FA was constructed by bonding the amino group of PAH with the carboxyl group of the targeting molecule folic acid(FA)by EDC/NHS reaction.The characterization results showed that the prepared MSN had a particle size of about 100 nm,and the channel structure was clear and well dispersed.After modifying with the Mn O2,the channel structure became fuzzy,which proved that Mn O2 was successfully coated.UV-Vis spectroscopy analysis showed that Mn O2 and FA were successfully modified on the surface of MSN in turn.In vitro chemodynamic performance analysis indicated that Mn O2 could effectively generate hydroxyl radicals and was a good chemodynamic therapeutic agent.Confocal laser scanning microscopy and MTT cytotoxicity experiments were used to evaluate the targeting and chemodynamic therapy effect of MSN@Mn O2-FA on SMMC-7721 and PC-12 cells.The obtained nanocomplex not only showed specific recognition to SMMC-7721 cancer cells with high expression of folate receptor(FR),but also demonstrated excellent chemodynamic therapy treatment effect.Chapter 3: The novel drug carrier,MSN-DOX@BSA/Cu S,was prepared by using the EDC/NHS reaction to combine the BSA/Cu S with amino MSN loaded with the chemotherapy drug DOX via the amide covalent bond.UVVis-NIR absorption spectra was used to investigate the absorption properties of the carrier.The results showed that the carrier had strong absorption in the near-infrared range of 800~1100 nm and could had excellent photothermal conversion property.In vitro drug release experiments showed that at a p H of 5.3 and a concentration of 10 m M GSH,the disulfide bond of the gated molecule BSA in the nanocomplex was broken,and the drug release was as high as 56%.Cytotoxicity experiments were used to evaluate the toxicity of the carrier and the synergistic effect of chemo-photothermal therapy.The unloaded MSN@BSA/Cu S showed low cytotoxicity.When MSNDOX@BSA/Cu S was co-incubated with cancer cells,the survival rate of the cells reduced to 50%.After the extra laser,the cells survived only 18%.The synthesized nano drug carrier could realize the synergistic treatment of photothermal therapy and chemotherapy,and had better killing effect on cancer cells.Chapter 4: The anticancer drug doxorubicin(DOX)was loaded in MSN by physical adsorption method,and dopamine was oxidized and selfpolymerized to form polydopamine(PDA),which modified on the surface of MSN.The manganese ion(Mn2+)was coordinated with the catechol on the surface of the PDA to further adsorb the photosensitizer methylene blue(MB),preparing a p H-responsive nanocomposite MSN-DOX@PDA-Mn/MB.Transmission electron microscopy(TEM)characterization results showed that the particle size of MSN was about 100 nm and a clear and orderly pore structure could be observed.Furthermore,PDA and Mn2+ were decorated on the surface of MSN successfully.Drug loading and release experiments showed that the drug loading contents of DOX and MB were 13.2% and 17.86%,respectively;in a weakly acidic environment at p H 5.3,the PDA shell was degraded,and both DOX and MB showed p H-stimulated responsive drug release.Cell imaging and cytotoxicity experiments showed that this nanocomplex effectively produced reactive oxygen species after being endocytosed by cancer cells.With the synergistic effect of chemophotodynamic-chemodynamic therapy,the cell survival rate was only 12%.The prepared nanocomposite MSN-DOX@PDA-Mn/MB had p H-responsive drug release properties,realizing the combination of chemotherapy,photodynamic and chemodynamic therapy,and improving the efficiency of tumor treatment.Chapter 5: We have summarized the research results of functional MSN as a nanocarrier in stimuli-responsive drug delivery,cancer targeting,and synergistic multi-therapy,and look forward to the application of MSN in cancer treatment.