Construction Of Tumor Microenvironment-responsive Nanoreactor Based On Metal-organic Framework Materials And Its Application In Multimodal Synergistic Treatment Of Breast Cance

Malignant tumor presents the characteristics of high incidence,low cure rate and easy recurrence,which is one of the major diseases that seriously threaten human health.Based on the tumor microenvironment（TME）characteristics such as slightly acidic,hypoxia and high levels of GSH and ATP,TME-responsive drug carrier can be designed to achieve pre-cise delivery and controllable release of drugs in tumor area,improving the killing effect on tumor cells while avoiding side effects on normal tissues.In recent years,metal organic frameworks（MOFs）have gained much attention in tumor therapy due to their high specific surface area and porosity,easy surface functionalization,good biocompatibility and bio-degradability.In addition,MOFs can encapsulate biomolecules such as DNA,proteins,and enzymes through the biomineralization process,effectively improving the stability of bi-omacromolecules,which greatly expands the application of MOFs in the biomedical field.In this thesis,a TME-responsive nanoreactor is constructed based on MOFs.The nanore-actor could gradually dissociate under specific stimuli in the TME,triggering the sequential release of multiple therapeutic agents and realizing the multimodal synergistic treatment of tumor,which provided a new research idea and method for the construction of nanotherapy platform and the development of nanotechnology in the biomedicine field.The main re-search content of this thesis is summarized as follows:1.Construction of tumor microenvironment-responsive nanoreactor based on metal organic framework biomineralization.Based on the principle of biomineralization,the TME-responsive nanoreactor is con-structed by using core-shell MOFs（ZIF-90@ZIF-67）as the carrier to encapsulate func-tional DNA molecules,enzymes and chemotherapeutic drugs.Firstly,Y-shaped DNA（Y-DNA）containing i-motif sequence and double-stranded linear DNA（L-DNA）containing DNAzyme sequence and disulfide bond（S-S）were designed.The sticky ends of Y-DNA and L-DNA are complementary to each other.The Y-DNA and L-DNA were used as struc-tural units to prepare DNA nanospheres（DNSs）by DNA self-assembly technology and DNSs were further employed to load chemotherapy drug doxorubicin（Dox）.Then,Dox/DNSs were encapsulated in ATP-responsive ZIF-90 to obtain Dox/DNSs@ZIF-90.Fi-nally,p H-responsive ZIF-67 was used to encapsulate glucose oxidase（GOx）and Dox/DNSs@ZIF-90 to prepare the final TME-responsive nanoreactor（Dox/DNSs@ZIF-90@GOx@ZIF-67）.The research results demonstrated that MOFs could efficiently load multiple therapeutic agents through biomineralization.Furthermore,the nanoreactor could dissociate in response to stimuli under simulated TME conditions（e.g.,slightly acidic,ATP,GSH）,realizing the sequential and controlled release of therapeutic agents.In conclusion,the TME-responsive nanoreactor based on MOFs biomineralization had great potential for applications in the fields of drug delivery and cancer therapy.2.Tumor microenvironment-responsive nanoreactor for multimodal synergistic therapy of breast cancer.Based on the good TME-responsive performance and excellent tumor killing potential,the Dox/DNSs@ZIF-90@GOx@ZIF-67 nanoreactor was used for multimodal synergistic tumor therapy,combining chemodynamic therapy,starvation therapy,gene therapy and chemotherapy.Upon internalized by tumor cells,the dissociation of ZIF-67 shell of the nanoreactor occurred in response to the acidic environment of tumor cells,releasing GOx and Co²⁺.The released GOx could catalyze glucose oxidation to generate H₂O₂ and glu-conic acid in tumor cells.On the one hand,the consumption of glucose cut off the energy supply of tumor cells to achieve starvation therapy;on the other hand,the produced H₂O₂could be converted into highly toxic·OH through Fenton-like reaction mediated by Co²⁺,thus achieving chemodynamic therapy.Then,the exposed ZIF-90 core of nanoreactor dis-sociated under the stimulation of H⁺and ATP in tumor cells,releasing Zn²⁺and Dox/DNSs.In response to the stimulation of GSH and acidic conditions,Dox/DNSs dissociated and released DNAzyme and Dox for gene therapy and chemotherapy,respectively.Both in vitro and in vivo results demonstrated that the nanoreactor exhibited synergistically enhanced antitumor effect and had broad application prospects in the field of nanomedicine.