Synthesis Of Multifunctional Mesoporous Nanocomposites And Their Application In Tumor Therapy

Cancer has always been the enemy of human health.At present,traditional chemotherapy(CT)is still the main anti-cancer treatment.However,common clinical chemotherapy drugs(such as paclitaxel and doxorubicin)still have many problems,such as poor solubility in water and easy rapid clearance in blood circulation.Subsequently,in order to solve the shortcomings of traditional therapies,some studies have proposed some new cancer treatment strategies,such as chemodynamic therapy(CDT)and photodynamic therapy(PDT).Among them,CDT mainly uses the acidic microenvironment of tumor cells as the reaction conditions,and uses transition metal-based compounds as catalysts to catalyze the Fenton or Fenton-like reaction of excess H₂O₂ in tumor cells to produce hydroxyl radicals(·OH)and other reactive oxygen species(ROS),which in turn oxidizes tumor cell membranes,DNA and protein molecules,and induces tumor cell apoptosis.In weakly alkaline normal cells or tissues containing a very small amount of H₂O₂,Fenton reaction or Fenton-like reaction cannot proceed.Therefore,CDT treatment is a highly effective treatment that specifically activates the tumor microenvironment and has certain safety to normal tissues.PDT uses a photosensitizer to generate a large amount of singlet oxygen(¹O₂)under laser irradiation of a specific wavelength,which in turn oxidizes nearby cells and induces cell apoptosis.In order to improve the therapeutic effect of traditional chemotherapy,other therapies(CDT,PDT)can be combined on the basis of chemotherapy to produce a synergistic therapeutic effect.In this paper,we designed and synthesized HMSNs and HMn O₂ as drug carriers,and modified the surface of the carrier with targeted molecules to achieve targeted tumor combined therapy.The results showed that on the basis of chemotherapy combined with other treatment methods(CDT,PDT),can improve the therapeutic effect of drug carrier in tumor cells.The specific work of this paper is mainly in the following three aspects:In the first chapter,we systematically introduce the application of tumor treatment,tumor targeting and mesoporous materials in the combined treatment of tumor.In the second chapter,we prepared hollow mesoporous silica nanoparticles(HMSNs)with a diameter of about 100 nm as drug carriers,using physical embedding and in-situ reduction of KMn O₄ to generate manganese dioxide(Mn O₂).The payload of the chemotherapy drug doxorubicin(DOX)and Mn O₂.In addition,a kind of p H responsive nano drug delivery system(DOX/Mn O₂@HMSN-imide-PEG-R₇-RGDS)was constructed by using the Schiff base bond formed by the amino group at the end of tumor targeting functional peptide(PEG-R₇-RGDS)and aldehyde modified HMSN(HMSN-CHO)In vitro drug release experiments proved that DOX/Mn O₂@HMSN-imide-PEG-R₇-RGDS has a significantly faster drug release behavior in the simulated acidic tumor environment(p H 5.0)than in the simulated physiological environment(p H 7.4).In addition,the results of in vitro cell experiments show that DOX/Mn O₂@HMSN-imide-PEG-R₇-RGDS can target tumor cells(He La)and release DOX quickly.At the same time,the Mn O₂ in the nano-drug-loaded particles reacts with the high concentration of glutathione(GSH)in the tumor cells to produce Mn²⁺with a Fenton-like effect.Mn²⁺reacts with the over-expressed H₂O₂ in tumor cells to generate·OH,exerting enhanced chemokinetic therapy.The cytotoxicity experiment proved that the combination of chemokinetic therapy and chemotherapy can produce high cytotoxicity to He La cells.In Chapter Three,we prepared hollow manganese dioxide(HMn O₂)nanoparticles with a diameter of about 100 nm,loaded DOX and Ce6 into HMn O₂,and coated them with folate modified polydopamine(PDA).When the nanoparticles are targeted into tumor cells,the tumor acid environment will promote the depolymerization and abscission of PDA,resulting in HMn O₂ being reduced to Mn²⁺by the over expressed GSH in cells,thus reducing the content of GSH and releasing DOX and Ce6.Mn O₂reacts with the over expressed H₂O₂ of tumor cells and triggers the decomposition of endogenous H₂O₂ to O₂,thus alleviating the hypoxic environment of tumor cells.Sufficient O₂ and GSH consumption can effectively enhance the efficacy of PDT and achieve enhanced chemotherapy photodynamic therapy.Cytotoxic experiments show that the combination of chemotherapy and photodynamic therapy can effectively kill tumor cells,while the toxicity to normal cells is very small.