Tumor Microenvironment-responsive Nanosystems Based On Metal-organic Frameworks For Precision Tumor Therapy

Cancer has become one of the most serious health problems in the world and a major challenge for the development of contemporary medicine.Traditional small-molecule drugs have serious limitations in their clinical applications due to the toxic and side effects,poor solubility,and low targeting.Nanomedicines can prolong drug half-life,improve drug solubility and enhance drug targeting,which greatly improves the anti-tumor effect and biological safety.Among them,the highly crystalline nanoscale metal organic frameworks（nMOFs）materials assembled by the coordination connection of metal ions（or metal clusters）and organic ligands are regarded as an emerging nanomedicine.With the advantages of tunable pores,diverse functions and good biocompatibility,nMOFs have shown broad application prospects in anti-tumor applications,and have become the most compelling cutting-edge materials in recent years.However,like other nanomedicines,nMOFs lack tumor specificity,cannot precisely treat tumors,and are prone to adverse reactions.Moreover,nMOFs are also limited by the complex tumor environment,such as tumor cells prone to multidrug resistance,limited light tissue penetration depth,tumor tissue hypoxia,etc.,resulting in poor anti-tumor effects.With the in-depth study of cancer,it is found that the occurrence and development of cancer are closely related to its microenvironment,including low pH value,high H₂O₂ concentration,high GSH concentration,overexpressed specific enzymes and hypoxia,etc.At the same time,the tumor microenvironment（TME）also provides new ideas for cancer-specific precision therapy.Therefore,this dissertation aims to construct TME-responsive nanosystems for precision tumor therapy by utilizing the tunable pores,diverse functions and ease of modification of nMOFs.Based on nMOFs,we have designed and constructed multiple TME-responsive nanosystems,which respectively utilize dual chemotherapy to effectively treat multidrug-resistant tumors;integrated photodynamic therapy with broad-spectrum anti-cancer effects to effectively treat deep tumors;the synergistic chemodynamic/photothermal/photodynamic trimodal therapy completely eliminates tumors.In vitro and in vivo experiments have demonstrated that these responsive nanosystems can achieve specific activation and precise tumor treatment effects with favorable biosafety.The details are as follows:（1）pH-responsive charge-reversed nMOFs@polymer composite system for precise combination chemotherapy of drug-resistant tumorsHierarchically porous nMOFs（HP-Ui O-66-NH₂）were first functionalized and modified,and then combined with pH-responsive orthoester monomer（OEAM）by radical polymerization to form pH-responsive polymer coating.Finally,two chemotherapeutic drugs,cisplatin and doxorubicin（CDDP and DOX）,were efficiently loaded to obtain a pH-responsive composite nanomedicines of CDDP@Ui O@DOX@POE（CUDPOE）.In a physiological environment,the nanomedicine remained stable,while in a mildly acidic environment,the negatively charged polymer coating responsively degraded and exposed positively charged nMOFs for charge reversal and drug release.In vitro and in vivo experiments showed that the composite nanomedicine could specifically respond to the low pH environment of tumors to enhance cellular internalization,tumor tissue penetration,and even efficient drug delivery to target cell nuclei.Therefore,this smart nanomedicine could performe a precise and effective therapeutic effect on drug-resistant tumors（MCF-7/ADR）.In addition,the nanomedicine exhibited good biological safety and could reduce the adverse reactions of anti-tumor drugs.（2）H₂O₂-activated dual nanozyme-active ultrathinMOF nanosheets for trimodal precision tumor therapyFirst,hierarchical porous porphyrin nMOFs（HP-PCN-224）were prepared as nanophotosensitizers,and then small molecules of luminol（Lum）and macromolecular hemoglobin（Hb）were efficiently loaded,thereby successfully preparing a new integrated photodynamic nanosystem（Lum+Hb@HP-PCN-224,LHHP）activated by H₂O₂.LHHP could be specifically activated by high concentration of H₂O₂ at the tumor site to generate near-infrared light and singlet oxygen（¹O₂）via chemiluminescence resonance energy transfer（CRET）.Hb could carry oxygen and catalyze the H₂O₂-Lum reaction,further enhancing the self-luminescence and ¹O₂ generation.In vitro and in vivo experiments showed that the nanosystem could achieve precise imaging and broad-spectrum PDT that was not limited by multidrug resistance after being specifically activated by H₂O₂ at the tumor site,overcomeing the limitations of light penetration depth,easy aggregation of photosensitizers,and tumor hypoxia in traditional PDT.This nolve nanosystem performed a good therapeutic effect on deep tumors.（3）H₂O₂-activated dual nanozyme-active ultrathinMOF nanosheets for enhanced trimodal precision tumor therapyFirst,a new type of Ce-TCPP（Fe）MOF（CTF）nanoparticles was prepared by solvothermal method using Ce³⁺and iron porphyrin molecule（TCPP（Fe））as metal nodes and ligands,respectively,and then ultrathin CTF nanosheets（NSs）were obtained by a simple ultrasonic exfoliation method.Under low pH value and H₂O₂conditions,CTF NSs exhibited efficient peroxidase-like（POD）and catalase-like（CAT）activities,generating hydroxyl radicals（·OH）and O₂,respectively.CTF NSs could also consume GSH and generate photothermal and photodynamic synergistic effects under a single laser irradiation.In vitro and in vivo experiments demonstrated that CTF NSs could specifically respond to TME and exert a precise chemodynamic/photothermal/photodynamic trimodal therapy.In addition,there was mutual promotion and synergy between different treatment modalities,which could completely eliminate tumors,thereby overcoming the defect that a single treatment mode cannot eradicate tumors.