Construction Of Autocatalytic Mesoporous Silica Nanosystem And Its Application In Tumor Cascade Therapy

In order to overcome the limitation of traditional tumor therapy,the synergistic therapy based on nano carrier has attracted attention.New tumor therapy strategies,including starvation therapy,chemodynamic therapy and hypoxia-activated chemotherapy,can specifically treat tumor in tumor microenvironment,and have been widely used in the biomedical field.In this paper,an autocatalytic mesoporous silica nanosystem（TPZ@Fe MSN-GOX）has been constructed by means of sol-gel,which has an excellent autocatalytic activity.It not only exhausts glucose to starve tumor,but also consumes O₂to enhance the tumor hypoxia,activating hypoxia-activated prodrugs TPZ and triggering chemotherapy,and concomitantly reduces p H and produces H₂O₂,improving the efficiency of iron-mediated chemodynamic therapy.About the autocatalytic nanosystem triggering the triple cascade therapy of starvation,chemotherapy and chemodynamic therapy,the main research and conclusions of this paper are as follows:（1）The iron-doped mesoporous silica nanocarriers（Fe MSN）were synthesized by sol-gel method and calcination,and Fe content measured by ICP-OES was 1.2 wt%.Fe MSN particle size was about 80 nm,with a high specific surface area of 228 m²g^-1and a pore size of 6.32 nm.The autocatalytic mesoporous silica nanosystem（TPZ@Fe MSN-GOX）was constructed by surface conjugation with glucose oxidase（GOX）and loading hypoxia-activated prodrugs tirapazamine（TPZ）on the surface of aminated Fe MSN according to amination reaction and immersion,the loading rates were 7-10%and 0.43%,respectively.（2）Using potassium titanate as an indicator of H₂O₂,it was demonstrated by UV-Vis that Fe MSN-GOX consumed glucose and produced H₂O₂.In the presence of chelating agent,it was demonstrated by ICP-OES that Fe MSN-GOX could release iron.Using TMB as an indicator of·OH,it was demonstrated by UV-Vis that Fe MSN catalyzed H₂O₂into highly toxic·OH under acidic environment,and the Fenton reaction was p H-and H₂O₂-dependent.Similarly,it was demonstrated by UV-Vis that Fe MSN-GOX consumed glucose and then converted produced H₂O₂to·OH.The enzyme-catalyzed/Fenton cascade reaction laid the foundation for the validation of TPZ@Fe MSN-GOX mediated triple cascade therapy.（3）Using DCFH-DA as a ROS probe,TPZ@Fe MSN-GOX was observed to produce ROS in PANC-1 cells by a fluorescence microscope.TPZ@Fe MSN-GOX had significant concentration-and time-dependent cytotoxicity to PANC-1 and 4T1 cells by MTT assay,and the IC₅₀of 24 h and 48 h were 1.31 and 0.35μg m L^-1,1.44 and 0.94μg m L^-1,respectively.The tumor-bearing mouse model demonstrated TPZ@Fe MSN-GOX could accumulate in tumor tissues after intravenous administration,significantly inhibit tumor formation and effectively prolong the survival period of tumor-bearing mouse.