Preparation And Study Of Microenvironment-responsive Iron Oxychloride Nanocomposites And Their Applications For Tumor Therapy

Tumors are known as disease with high morbidity and mortality,which seriously threatens the human health.At present,the clinical treatment of tumors mainly depends on surgery,radiotherapy,chemotherapy,and other means,which have many problems,such as poor efficacy,significant side effects,and easy metastasis and recurrence.Therefore,there is a current need to develop novel and efficient tumor treatment methods.Chemodynamic therapy（CDT）is a tumor treatment technology that has emerged in recent years.Its principle is to use Fe and other Fenton catalysts to decompose endogenous H₂O₂ in tumors and generate strong oxidative hydroxyl radicals（·OH）which can destroy and kill tumor cells.Compared with traditional tumor treatment methods,CDT has the advantages of low invasiveness,no drug resistance,and no dependence on external stimulation,and the therapeutic effect is not limited by tissue hypoxia and penetration depth,showing good development potential and received extensive attention.However,CDT-based tumor therapy still has some problems.For instance,the tumor microenvironment（TME）with weakly acidic condition significantly limits the catalytic activity of Fenton catalysts,and the limited H₂O₂concentration in TME also limits the tumor cell killing efficiency.In addition,the Fenton catalysts without the TME-responsive activation often cause collateral damage to normal cells.Therefore,it is of great significance to further improve the therapeutic efficacy of CDT and enhance its selectivity.Aiming at the above problems,this thesis iron oxychloride（FeOCl）nanomaterials were prepared as a new type of Fenton catalyst.Two types of TME-responsive FeOCl nanocomposites,combined with chemotherapeutic drugs and calcium ion releasing materials,were developed for efficient combined treatment of tumors.The main contents of the thesis are as follows:1.Preparation and characterization of PAD@FeOCl/DOX-BSAFeOCl nanodots（FeOCl NDs）and disulfide-crosslinked polymer nanospheres（poly（AA-co-DMA）,PAD）were prepared by mechanical exfoliation and precipitation polymerization,respectively.Subsequently,FeOCl NDs,doxorubicin（DOX）,and bovine serum albumin（BSA）were loaded onto PAD to prepare PAD@FeOCl/DOX-BSA nanocomposite（PFDB）,and its morphology,composition,catalytic property,degradation property,drug release property,cytotoxicity,and colloidal stability were studied.The experimental results show that FeOCl NDs,DOX,and BSA can be successfully loaded on PAD nanospheres,and the prepared PFDB has a uniform morphology and an average size of about 200 nm;PFDB has good Fenton catalytic performance and can be responsively degraded in TME to release the loadings,and has good biocompatibility and colloidal stability.2.Study of the therapeutic effect of PFDB for the combined treatment of tumorsPFDB was studies as a microenvironment-responsive nanoagent for combined CDT-chemotherapy of tumors in vitro and in vivo.When PFDB reaches tumor tissues through enhanced penetration and retention（EPR）effect,PAD is degraded in glutathione（GSH）and weakly acidic microenvironment,causing the release of FeOCl NDs and DOX.FeOCl NDs can catalyze H₂O₂ to generate·OH,destroying the structure and function of tumor cells;at the same time,DOX can be effectively enriched in tumor tissues to realize tumor chemotherapy.The results of cell experiments and mouse experiments showed that PFDB-based CDT-chemotherapy combination therapy can effectively inhibit tumor growth,and its efficacy is significantly higher than that of single treatment mode.In addition,the results of toxicity experiments showed that PFDB has good biocompatibility.3.Preparation and application of FeOCl-GOx@Ca CO₃-PEG nanosheetsFeOCl nanosheets（FeOCl NSs）were prepared by ultrasonic method,and glucose oxidase（GOx）,calcium carbonate（Ca CO₃）,and polyethylene glycol（PEG）were modified on their surfaces to prepare FeOCl@GOx/Ca CO₃-PEG nanosheets（FGCP NSs）.Subsequently,the morphology,composition,catalytic performance,degradation property,Ca²⁺release performance,colloidal stability,and cytotoxicity were characterized.In acidic TME conditions,Ca CO₃ in FGCP NSs is degraded,releasing FeOCl NSs,GOx,and Ca²⁺.GOx catalyzes the oxidation of glucose to generate H₂O₂and gluconic acid,which subsequently increases the H₂O₂ level,lowers the environmental p H,enhances the catalytic efficiency of FeOCl,and improves the efficacy of CDT;at the same time,Ca²⁺can cause cellular calcium overload and induce apoptosis.In vitro experiments showed that FGCP NSs can respond to weakly acidic microenvironment and glucose,significantly increase the level of oxidative stress in tumor cells,cause mitochondrial dysfunction,lead to tumor cell apoptosis,and efficiently kill tumor cells through the combination of CDT and calcium overload.