Application Of Ce And Co Doped Hollow Mesoporous Silica Spheres In Tumor Therapy

Because chemodynamic therapy（CDT）does not require external stimulation and has less side effects on normal cells,it has become a popular method for cancer treatment.However,the low catalytic efficiency and off-target side effects of the Fenton reaction limit its biomedical applications.What’s more,the therapeutic effect of CDT mainly depends on the amount of·OH generated,and the antioxidant glutathione（GSH）in cancer cells will consume the generated·OH,which makes the single CDT treatment unsatisfactory.There are mainly two strategies to enhance the therapeutic effect of CDT.One starts from the internal environment of the tumor,and improves the catalytic efficiency of nanocatalysts by improving the tumor microenvironment（such as increasing the content of H₂O₂,eliminating reducing substances,and reducing pH value）.The second is that CDT can be combined with other treatments to enhance the anti-cancer effect.Mesoporous silica is a commonly used drug delivery carrier,with the advantages of tunable size and pores,large surface area,high pore volume,easy functional modification,etc.By adjusting the pore size of MSNs,different sized therapeutic agents can be delivered to the tumor site.However,there is still some controversy about the degradation characteristics of MSN,and it may take several weeks for MSN to fully degrade in biologically relevant media.Doping inorganic metals into the silicon-oxygen framework alters the inherent degradation properties of MSNs,making them ideal for biodegradation,thereby enabling controlled drug release.In this thesis,we successfully doped Ce and Co into the silicon-oxygen framework by hydrothermal method to prepare two kinds of metal-doped mesoporous silica nanoparticles.The doping of metal ions changes the biodegradation properties of silica,making it have better biodegradation properties.More importantly,different properties can be imparted to the materials,and the two materials have the effect of CDT through the Fenton-like reaction mediated by the doped cerium and cobalt.In addition,cerium-based materials often have catalase-like capabilities,while cobalt-based materials can be used as magnetic resonance imaging contrast agents.Based on these two vectors,we designed two strategies to enhance the therapeutic effect of CDT.First,by improving the tumor microenvironment,high-valent metal ions are used to consume GSH to prevent tumor cells from clearing the generated ROS through a self-regulatory mechanism,and the as-prepared cerium-doped hollow spheres are combined with the drug Saikosaponin A（SSA）to further enrich ROS at the tumor site.Second,SDT and CDT are combined to increase the killing ability of the material to cancer cells.The main content of this thesis is divided into the following four chapters:In the first chapter,the drug delivery system based on mesoporous silica nanoparticles is reviewed,and the chemodynamic therapy and the strategies commonly used to enhance the therapeutic effect of CDT are summarized.Finally,the research ideas of this paper are proposed.In the second chapter,SSA@Ce-HMSN-PEG nanocomposites were designed and synthesized.First,Ce-HMSN nanoparticles of uniform size were synthesized by hydrothermal method,with obvious cavity structure and pores,which could be used to load the drug SSA.Through Ce³⁺-mediated Fenton-like reaction,endogenous H₂O₂ is converted into highly toxic hydroxyl radicals,causing damage to cancer cells and realizing chemodynamic therapy.In addition,the presence of Ce⁴⁺makes the material have catalase-like properties,which can relieve hypoxia at the tumor site.At the same time,Ce⁴⁺can consume overexpressed GSH in cancer cells,further enhancing the effect of CDT.The drug SSA can generate a large amount of superoxide anion in cells,which further enriches ROS in cancer cells.Expanded oxidative stress in tumor tissue causes greater damage to cancer cells,resulting in a significant inhibitory effect on tumors.In the third chapter,two kinds of mesoporous cobalt silicate spheres with different morphologies were prepared by using MSN and SiO₂ as templates,respectively,and the properties of the two mesoporous cobalt silicate spheres were compared.The experimental results show that both types of mesoporous cobalt silicate spheres can be used as novel inorganic sonosensitizers to generate cytotoxic ROS under the trigger of ultrasound,while the mesoporous cobalt silicate spheres synthesized with MSN as a template have better sonodynamic performance.The factors that affect SDT are further explored,and the sonodynamic effect of the material is closely related to the formed wrinkles on the surface and the pores in the material.Based on the Fenton-like reaction of cobalt-based materials,both types of mesoporous cobalt silicate spheres can be used for CDT.Meanwhile,mesoporous cobalt silicate spheres can be used as T₂-weighted magnetic resonance contrast agents,which have the potential to integrate tumor diagnosis and treatment.In the fourth chapter,the research content and results of this thesis are summarized,and its further application is prospected.