Functional Modification Of Hollow Mesoporous Silica Spheres Doped With Iron Or Manganese And Their Application In Sonodynamic/Gas Synergistic Treatment Of Tumors

Sonodynamic therapy(SDT),which is based on sonosensitizer triggered by ultrasound to produce reactive oxygen species(ROS)and effectively kill tumor cells,is a new tumor therapy method and has attracted wide attention due to its non-invasiveness,high tissue penetration depth and low side effects.However,the hypoxia characteristics of the tumor microenvironment and the high expression of glutathione limit the production efficiency of ROS and the therapeutic effect of SDT.There is an urgent need to combine gas therapy,chemodynamic therapy(CDT)and other new green treatment methods to make up for the shortcomings of SDT.Therefore,it is of great significance to develop a multifunctional sonosensitizer that integrates two or three modes of SDT/gas therapy/CDT to obtain an integrated sonosensitizer with imaging and therapeutic functions,which is of great significance to timely,accurate diagnosis and safe and efficient treatment of tumors.T The hollow mesoporous silica nanoparticles doped with metal elements have a series of advantages such as a huge cavity structure,an inner and outer surface that is easy to be chemically modified,efficient guest molecule loading efficiency,acid-responsive skeleton degradation to release metal ions and drugs,and excellent biocompatibility.Therefore,they provide a strategy for the construction of a multi-functional nano-platform for the combination therapy of SDT and other treatment methods.In this thesis,guided by the practical application in convenient,safe,and efficient diagnosis and treatment of tumors,we use hollow mesoporous silica nanoparticles doped with metal elements as functional carriers,focus on the controllable synthesis and functional modification of the nanoparticles,and carry out the research on MRI imaging,SDT/gas therapy/CDT synergistic treatment application and biological effect of the obtained nanoplatforms.The main content includes the following four chapters.In chapter one,we summarize the killing mechanism of SDT on tumor cells,the effect of tumor microenvironment on sonodynamic efficacy,and the improvement methods proposed for the influencing factors of tumor microenvironment.Then the application of several common gases in tumor treatment is briefly introduced,and the research ideas of this thesis are proposed.In chapter two,we have designed and synthesized iron-doped hollow mesoporous silica nanoparticles(Fe-HMSNs),and further modified SO₂ gas donor(DNs)on the surface and wrapped the cell membrane to construct CCM@Fe-HMSNs-DNs for enhancing oxidation stress and improving tumor treatment effect.In organisms,the reactive oxygen and antioxidant systems are in equilibrium.When the balance is broken,especially when the antioxidant system is damaged,it will cause oxidative stress and cause cytotoxicity.The constructed CCM@Fe-HMSNs-DNs nanomaterials increase the aggregation of nanoparticles at tumor sites under homologous targeting.Under the action of glutathione,the nanosystem releases SO₂ gas and iron ions.SO₂ can destroy the antioxidant system by affecting the antioxidant system of cells,that is,reducing the contents of superoxide dismutase(SOD),glutathione peroxidase(GPX)and glutathione(GSH)in cells.In addition,the nanosystem also has sonodynamic and chemodynamic effects.Nanoparticles will produce a large amount of ROS after ultrasound irradiation.At the same time,the tumor microenvironment promotes the release of iron ions.The Fenton reaction between iron ions and hydrogen peroxide at the tumor site produces ROS.Therefore,CCM@Fe-HMSNs-DNs changes the redox balance in the cell by inhibiting the antioxidant system and increasing the content of ROS,which expands the effect of oxidative stress,thereby improving the SDT/gas/CDT combined treatment effect.In chapter three,the hollow mesoporous silica nanoparticles doped with manganese(MH)have been designed and synthesized,and the cavity and surface of the nanoparticle are modified with sonosensitive agent Bengal rose(RB)and NO gas donor(SNO),respectively,to construct MH-SNO@RB for SDT/NO gas synergic therapy.In recent years,SDT has attracted widespread attention in the field of cancer treatment due to its non-invasiveness and deep tissue penetration.However,the therapeutic effect of SDT is still limited by the hypoxic environment and high levels of GSH in solid tumors.Synergistic treatment strategy can effectively improve treatment efficiency.In this chapter,the MH-SNO@RB nanoplatform can enhance cancer treatment effects through SDT and nitric oxide(NO)gas therapy.The slightly acidic and reducing tumor microenvironment accelerates the sustainable release of Mn ions from the skeleton,which makes MH-SNO@RB useful as a MRI contrast agent for tumor sites.More importantly,ultrasound simultaneously triggers the production of NO and the release of ROS.The synergistic effect of sonodynamic therapy and NO gas therapy can effectively kill cancer cells and inhibit tumor cell growth.In addition,MH-SNO@RB has excellent biocompatibility and biosafety.In chapter four,we summarize the research content and results of this paper,and prospect the application prospects of related nanomaterials.