Investigation Of Manganese-Based Nanodrug Construction And Anti-tumor Effect

Cancer,also known as malignant tumor,is one of the major public health problems that seriously threatens human health.The current treatment methods for cancer mainly include chemotherapy,surgical resection,radiotherapy and so on.Surgical resection refers to the direct removal of tumor tissue.It is generally used to treat solid tumors in clinical practice and its therapeutic effect is very significant.Radiotherapy refers to the use of various types of radiation to irradiate tumors to kill or inhibit excessive proliferation of cancer cells.Chemotherapy refers to the entry of chemical drugs into the blood and tumor tissues to kill tumor cells.Currently,chemotherapy is still one of the most commonly used methods.However,traditional chemotherapy has its disadvantages.Chemotherapeutic drugs act on the whole body and cause serious side effects on normal tissues,and the efficacy of the drugs on the lesions is greatly reduced.Severe side effects and low efficacy of chemotherapy have become the main causes of death in chemotherapy patients.Therefore,it is particularly important to rationally develop and optimize cancer treatment strategies with good biosafety and high efficiency.In the first chapter of the thesis,some new strategies of cancer treatment and related researches on manganese in the treatment of cancer were reviewed,mainly involving new strategies such as delivery proteins,photothermal therapy,photodynamic therapy,nanozyme catalytic therapy,etc.The methods synergistically enhance tumor treatment;then the application of manganese in nanoenzymes in nanocatalytic therapy and multimodel imagings are introduced.Finally,manganese-based nanoenzymes in the tumor microenvironment catalyze the production of oxygen to alleviate the hypoxic microenvironment of tumors,and then enhance the effect of tumor therapy.The second chapter introduces the dual-function nanoreactor(GOx-MSN@MnPc-LP)we designed.The hydrophilic glucose oxidase is loaded on the mesoporous silica through electrostatic interaction,and the hydrophobic manganese phthalocyanine is loaded in the phospholipid bilayer of liposomes through hydrophobic interaction,and finally the mesoporous silica and liposomes self-assemble through electrostatic interaction obtain a nanoreactor.Both the results of the experiments in vitro and in vivo show that the nanoreactor can not only catalyze the conversion of glucose into toxic hydrogen peroxide,but also generate singlet oxygen under 730 nm laser irradiation,thereby synergistic ally inhibiting tumor growth.The Hematoxylin-Eosin(H&E)experiment showed that the nanoreactor had no effect on the main organs of mice,which proved the biosafety of the nanoreactor.In this work,by designing a suitable carrier for intracellular protein delivery,it not only effectively protects protein invariance,but also significantly reduces toxic and side effects.In Chapter 3,a manganese-based single-atom nanoenzyme(Mn/PSAE)was designed and developed for synergistic nanocatalysis and photothermal therapy.Mn/PSAE can not only specifically catalyze the decomposition of hydrogen peroxide into toxic hydroxyl radicals in the tumor microenvironment,but also cascade the conversion of hydrogen peroxide into oxygen,and then into toxic superoxide anions,thereby inducing apoptosis.In addition,Mn/PSAE also has a photothermal effect.Mn/PSAE with the high-temperature damaged cells can catalyze the production of cytotoxic reactive oxygen species,which significantly enhances the antitumor effect of the single atom enzyme.We performed a series of biochemical experiments to verify the mechanism of Mn/PSAE inhibiting tumor growth,including the determination of various enzyme-like activities,detection of reactive oxygen species,and mitochondria changes in membrane potential,integrity of lysosomal membranes,and lipid peroxidation in cells.These experiments further prove that the Mn/PSAE induces cell apoptosis by catalyzing the production of reactive oxygen species through hydrogen peroxide overexpressed at the tumor site.In vivo experiments proved that Mn/PSAE can effectively inhibit tumor growth and has high biological safety.This work utilizes the chemical properties of the material to construct a green and efficient nano-catalyst,which improves the catalytic efficiency in the physiological environment and reduces the toxic and side effects to patients.In Chapter 4,a nano-flower manganese copper sulfide(PCMS NFs)nanoparticles was designed and prepared for multimodal imaging-guided nanocatalytic therapy and NIR-? photothermal therapy.PCMS NFs specifically decomposes tumor over-expressed hydrogen peroxide into oxygen in the tumor microenvironment(TME),and then convert the oxygen into toxic superoxide anions,thereby inducing cancer cell apoptosis.Under NIR-? laser irradiation,PCMS NFs can efficiently generate thermal effects,and synergistically inhibit tumor growth with catalytic therapy.In addition,PCMS NFs can also perform multimodal imaging including thermal imaging.photoacoustic imaging,and magnetic resonance imaging that can detect the location and growth of tumors in real time,to achieve integration of diagnosis and therapy.In Chapter 5,a diagnosis and treatment platform was constructed for tumor microenvironment(low pH/overexpressed H2O2)responsive to enhanced photodynamics through biomineralization.We constructed a cavity-loaded Ce6 and manganese dioxide nanoparticles in ferritin(Ce6/Ftn@MnO2).This design makes full use of the inherent properties of proteins and nanoparticles,containing good biodegradability,good biocompatibility and high tumor accumulate ability.At the same time,Ce6/Ftn@MnO2 can also be used for fluorescence imaging to accurately track drug accumulation and tumor location in vivo.In vitro experiments have shown that Ce6/Ftn@MnO2 with near-infrared light treatment not only effectively improves the tumor hypoxic microenvironment at the tumor site and significantly increases the efficiency of inhibiting tumor growth,but also has high biological safety.Therefore,this study provides new insights for biomineralization synthesis and builds a therapeutic platform for tumor microenvironment response.By continuously catalyzing oxygen production,the tumor hypoxic mircoenvironment is improved,thereby significantly enhancing the anti-tumor efficacy of PDT.