Tumor Microenvironment Regulation For Efficient Sensitization Of Chemodynamic Therapy

The abnormal metabolic behavior of tumor cells causes them to exhibit a redox microenvironment different from that of normal cells,mainly characterized by the abundance of hydrogen peroxide（H₂O₂）and glutathione（GSH）.The unique redox microenvironment of tumor tissue is not only closely related to the development of tumor,but also makes tumors tolerant to various forms of treatment.Chemodynamic therapy（CDT）is a new class of unique and specific tumor treatment modality,which is based on the Fenton/Fenton-like reactions occurred in the high H₂O₂ content tumor microenvironment.However,the relatively limited amount of H₂O₂ and the high concentration of antioxidant GSH in tumor cells severely limit the therapeutic effect of CDT.Therefore,it will help to enhance the therapeutic effect of CDT by regulating the redox microenvironment in tumor cells,which also has important academic value and clinical significance to promote the development of CDT.Based on the realization of efficient tumor CDT,three nanoplatforms with both tumor microenvironment response and regulation functions were designed and prepared,and initially achieve efficient CDT therapy for breast cancer.The main research contents are as follows:1.Functionalized dendritic mesoporous organosilica nanoparticles（DMON）modulate cellular redox microenvironment for enhanced tumor CDT.The limited intracellular H₂O₂ and GSH-based reducing substances in tumor cells severely limit the therapeutic effect of CDT.Based on this,DMON@Fe⁰/AT nanoparticles were designed and synthesized in this study to enhance the therapeutic effect of CDT by elevating the intracellular H₂O₂ concentration and depleting intracellular GSH in tumor cells.In the mildly acidic tumor microenvironment,on-demand Fe²⁺and AT are intelligently released from DMON@Fe⁰/AT nanoparticles,while S-S bond-riche DMON is exposed.By inhibiting intracellular catalase activity,AT promotes intracellular H₂O₂accumulation and provides sufficient substrate for the Fe²⁺-mediated CD;Meanwhile,the S-S bond of DMON can effectively scavenge intracellular GSH,which will reduce the depletion of H₂O₂ and resistance to oxidative stress,and significantly enhancing the therapeutic effect of CDT.What is worth mentioning,the effective CDT can effectively attack mitochondria and downregulate the expression of ferroportin1（FPN1）,which can disrupt the cellular iron metabolism system,leading to the desired retention of iron in the cytoplasm.The above three effects were superimposed to significantly enhance the tumor CDT efficacy.Both in vitro and in vivo experiments showed that DMON@Fe⁰/AT had more efficient CDT therapeutic effects compared with amorphous iron nanoparticles（Fe⁰）alone.Overall,this work enhanced CDT efficacy from the dual perspective of modulating iron metabolism and redox state in tumor cells.2.Copper-Doxorubicin（Cu-DOX）coordination assemblies coated Ca O₂nanoparticles for drug-resistant tumor therapy.With the assistance of glutathione S-transferase（GST）,chemotherapeutic drugs can be coupled with the sulfhydryl group of GSH to form GS-drug binary complexes,and then pumped out by the ATP-dependent GS-X cell membrane protein,which severely reducing the intracellular chemotherapeutic drug concentration and leading to drug resistance.Compared with wild-type tumor cells,drug-resistant tumor cells elevate the intracellular GSH content by up-regulating the expression ofγ-glutamylcysteine synthetase（γ-GCS）,which in turn reduced the sensitivity of cells to chemotherapeutic drugs.In addition,the high level of GSH in drug-resistant tumor cells also poses a great challenge for efficient CDT.Based on this,we prepared polyethylene glycol（PEG）-modified Cu-DOX coated Ca O₂（Ca O₂@Cu-DOX@PEG,CCDP）nanoparticles.CCDP nanoparticles can overcome tumor drug resistance by continuously depletion of intracellular GSH and intense CDT through intracellular activated"self-promoted cascade reaction（SPCR）"strategy.Once CCDP nanoparticles are endocytosed by drug-resistant tumor cells,the intracellular overexpressed GSH is able to unlock the Cu-DOX coordination structure,releasing Cu⁺and DOX.While,the exposed Ca O₂ nanoparticles can decompose to H₂O₂ and Ca²⁺persistently.Subsequently,H₂O₂ is catalyzed by Cu⁺to generate highly toxic·OH via intracellular Fenton-like reaction.During the degradation of CCDP,a large amount of intracellular GSH is depleted consistently from drug-resistant cells,which not only overcomes the classical DOX resistance mechanism of tumor cells,but also significantly enhances the efficacy of CDT.The intracellular GSH-unlocked“SPCR”strategy we proposed can achieve efficient treatment of drug-resistant tumors,while also provides a new idea for efficient CDT and drug-resistant tumor therapy.3.Chlorogenic acid-ferric ion nanosheets enhanced tumor chemodynamic and immunotherapy through“self-circulating cascade amplification effect”.The redox tumor microenvironment of not only limits the therapeutic effect of CDT,but also is closely related to tumor immune tolerance.Based on this,we prepared an acid-sensitive chlorogenic acid-ferric ion nanosheets（CAFNSs）to selectively enhance tumor CDT and immunotherapy through the autoxidation reaction of chlorogenic acid（CA）.Once CAFNSs is endocytosed by tumor cells,it will decompose into CA and Fe³⁺in the acidic environment of lysosomes.Then,excessive O₂.^-and O₂ in tumor cells are converted to H₂O₂ through the autoxidation reaction of CA.Subsequently,H₂O₂ is catalyzed to generate highly toxic·OH via Fe³⁺mediated Fenton reaction,causing immunogenic cell death（ICD）and promoting cytotoxic T cells infiltration.In addition,CAFNSs can also promote the differentiation of tumor-associated macrophages（TAMs）to the antitumor M1 type by elevate the ROS level in TAMs,which will activate their phagocytosis and antigen presentation ability.With the combination of anti-PD1,CAFNSs not only exhibited excellent killing effect on the primary tumor,but also exerted a significant inhibitory effect on the growth of distal tumors.In this work,we regulated tumor redox microenvironment by CA,which achieves the enhancement of tumor CDT and immunotherapy at the same time.