Preparation Of Metal Organic Framework-based Nanosystems For Chemodynamic Therapy Properties Of Tumors

Chemodynamic therapy is a new therapeutic approach that is triggered by endogenous chemical conditions in the tumor microenvironment,but not by exogenous stimuli.Due to the acidic tumor microenvironment and overexpression of hydrogen peroxide,tumor cells produce more cytotoxic hydroxyl radicals through Fenton or Fenton-like reactions,which leads to irreversible damage of biological macromolecules such as DNA and lipids.The therapy has the advantages of tumor specificity,high selectivity,low systemic side effects,and no need for external stimulation,which is a promising strategy for tumor treatment.However,the application of nanoparticle in chemodynamic therapy still has some limitations,such as the small specific enrichment of nanoparticle at the tumor site,low therapeutic efficiency,poor biosafety,and side effects.In this study,starting from the special microenvironment of tumors and using metal-organic framework materials as drug carriers,four new types of efficient and tumor-specific nanosystems were designed and synthesized for enhancing chemodynamic therapy.The specific research content of this paper is as follows:The porous Prussian blue nanoparticle was prepared by chemical etching,and polyethylene glycol was further modified withβ-lapachone and lauric acid to construct the MPB-Lap/La@PEG nanoparticle drug carrier system.The limitations of low hydrogen peroxide content at the tumor site,low Fenton reaction efficiency,and glutathione overexpression in the tumor microenvironment were overcome.Under the irradiation of an 808nm laser,the temperature of the system increased and the photothermal treatment effect was obtained,and the photothermal conversion efficiency was 21.15%.Temperature increase not only accelerated the release ofβ-lapaquone and enhanced the expression of NQO1 protein,but also increased the Fenton reaction rate.In addition,β-lapaquone interacts with NQO1 protein to produce hydrogen peroxide,while consuming the reduced coenzyme in the cell,inhibiting the synthesis of glutathione.The experimental results show that the material can achieve the photothermal enhanced chemodynamic therapy effect driven by near infrared light.In the tumor-bearing mouse model,the tumor inhibition rate reached 89.11%after 14 days of treatment.To solve the problems of the low loading capacity of porous materials and thermal damage to healthy tissues caused by photothermal treatment,hollow Prussia blue nanoparticle were prepared under controlled chemical etching conditions,loadedα-cyano-4-hydroxy-cinnamic acid（CHC）and lactate oxidase,and modified with polyethylene glycol to obtain HPB-CHC/LOD@PEG nanoparticle drug carrier system.The system reduces lactic acid content in two ways.On the one hand,CHC released in the tumor microenvironment can inhibit the expression of monocarboxylate transporters and block the uptake of tumor lactate,thus disrupting the balance of lactic acid inside and outside the tumor.On the other hand,the released lactate oxidase can catalyze the production of hydrogen peroxide from lactate,and achieve efficient chemodynamic therapy.At the same time,the reduction of lactate also improved the acidity value of the tumor microenvironment,inhibited the growth and metastasis of colon cancer cells,and the invasion and metastasis rates were 9.24%and 7.91%,respectively.After14 days of treatment,the tumor inhibition rate of the tumor-bearing mice reached 87.19%.To solve the problems such as the slow degradation rate of Prussian blue nanoparticles in vivo and harsh synthesis conditions of porous or hollow structures.The Cu/ZIF-8@DSF-GOD@Mn O₂ nanodrug carrying system was successfully constructed by one-step synthesis of copper-doped zeolite-like imidazole frame nanomaterial,loading with disulfiram and glucose oxidase,and in situ growth of manganese dioxide.The manganese dioxide in the system can consume glutathione in the tumor microenvironment,relieve tumor hypoxia,and enhance the reaction of glucose oxidase catalyzing the endogenous glucose to hydrogen peroxide.The system can degrade rapidly in the acidic microenvironment of tumors,release copper ions and disulfiram together,and further transform into cytotoxic substances to achieve disulfiram-mediated chemotherapy.In addition,the resulting monovalent copper ions can form hydroxyl radicals with hydrogen peroxide in a highly efficient Fenton-like reaction.After 14 days of treatment,the tumor inhibition rate of this system was as high as 79.87%,which was significantly higher than that of chemotherapy group alone（44.45%）and chemodynamic therapy group（50.94%）,and the combination of chemotherapy and chemodynamic therapy was realized.Aiming at the problems of low load and complex synthesis process in the above research.Based on the study in the previous chapter,the solid and hollow structures of ZIF-8/67/90@Mn O₂ were synthesized by adjusting the ratio of reactants.After comprehensive analysis and comparison,hollow ZIF-67@Mn O₂ was selected as the drug transport carrier,loaded with L-arginine and modified with polyethylene glycol,to obtain ZIF-67-H@Mn O₂-Arg@PEG nanodrug-carrying system with various enzyme activities.In the tumor microenvironment,the material can generate hydroxyl radicals through a Fenton-like reaction to achieve chemodynamic therapy.In addition,the system also alleviates tumor hypoxia through catalase-like activity,and cascades to enhance the activity of oxidase to produce superoxide anion.The released L-arginine can generate nitric oxide catalyzed by cellular endogenous enzymes,and then form peroxynitrite with superoxide anions to achieve ferroptosis of tumor cells induced by reactive oxygen species and reactive nitrogen species.In addition,manganese dioxide can consume overexpressed glutathione in tumors,while the produced peroxynitrite can down-regulate the expression of glutathione reductase 4,thus inhibiting the regeneration of glutathione and reducing the content of intracellular glutathione.After 14 days of treatment,the tumor inhibition rate was as high as 85.80%.