Study On Preparation Of Novel Composite Nanomaterials To Enhanced Chemodynamic Therapy For Antitumor And Antibacterial

The number of deaths from malignant tumors and bacterial infections is increasing every year worldwide.Therefore,development of novel therapeutic strategies for tumors and bacterial infections remains an important research topic.In recent years,Chemodynamic therapy（CDT）,as a promising treatment,attracted more attention from the international academic community.Unlike traditional antitumor and antibacterial therapeutic,CDT uses the microenvironment to activate Fenton or Fenton-like reactions to generate strong oxidative hydroxyl radicals（·OH）for antitumor and antibacterial specific therapies,fully reflecting the cross-fertilization of Fenton chemistry,materials science and biomedicine.However,in the actual application,the nanomaterial itself and the poor environmental conditions limit the ideal therapeutic effect.This thesis focuses on solve the lack of substrate（H₂O₂）in the treatment process of CDT and the unsatisfactory therapeutic effect of single treatment modality,Four novel composite nanotherapeutic systems were designed for antitumor and antibacterial therapy,and explored the potential applications of composite nanomaterial-mediated CDT therapies for enhanced antitumor and antibacterial therapy.The main research and conclusions of this thesis are as follows:（1）Circulating self-supplied H₂O₂/O₂ composite nanosystem synergistic enhancement of CDT-starvation therapy（ST）antitumor:In this study,a novel composite nanosystem ZnO₂@Au@ZIF-67 nanoparticles（NPs）was constructed and used to achieve CDT synergized with ST in response to tumor microenvironment（TME）to improve the therapeutic effect on tumors.First,in the acidic TME,the p H responsive decomposition of the zeolite imidazolium framework-67（ZIF-67）shell triggered the release of the Fenton-like catalyst Co²⁺,after the exposed zinc peroxide（ZnO₂）reacted with H₂O（H⁺）to generateO₂ and hydrogen peroxide（H₂O₂）.The generatedO₂ could alleviate hypoxia in the TEM and interact with ultra-small Au NPs originally coated on ZnO₂to catalyze intracellular glucose and to produce another source of H₂O₂.While the glucose consumption caused the starvation of tumor cells,the generated H₂O₂ from dual sources reacted with the catalyst Co²⁺to generate highly toxic·OH for CDT.Achieving efficient CDT-ST synergistic therapeutic effects.Based on the results of in vivo and ex vivo experiments,the composite nanosystem has the ability to synergistically enhance the tumor therapeutic effect of CDT-ST.（2）Mild photothermal controlled releaseβ-lapachone composite nanosystem combined with CDT for enhanced tumor therapy:In this study,a composite nanosystem CV@Pt Fe/（La-PCM）NPs was constructed.We employed carbon vesicle nanoparticles（CV NPs）with high near-infrared（NIR,808 nm）photothermal conversion efficiency as carriers.Ultrafine platinum iron alloy nanoparticles（Pt Fe NPs）were grown in situ on the CV NPs,where the highly porous nature of the resultant CV@Pt Fe NPs was employed to encapsulate a drug,β-lapachone（La）,and phase-change material（PCM）.As a novel multifunctional nanocatalyst CV@Pt Fe/（La-PCM）NPs can exhibit a NIR-triggered photothermal effect and activate cellular heat shock response,which upregulates the downstream NQO1 via HSP70/NQO1 axis to facilitate bio-reduction of the concurrently melted and released La.Moreover,sufficientO₂ is supplied by CV@Pt Fe/（La-PCM）NPs catalyzed at the tumor site to reinforce the La cyclic reaction with abundant H₂O₂generation.This promotes the bimetallic Pt Fe-based nanocatalysis,which breaks H₂O₂ down into highly toxic·OH for CDT.Not only that,the mild photothermal effect can effectively avoid the damage to normal tissues by excessive heat and exert the desired effect.The results suggest that the composite nanosystem overcomes the limitation of H₂O₂ deficiency through endogenous stimulation and synergizes PTT under mild conditions to achieve enhanced CDT tumor therapeutic effects.（3）Ag₂O₂ composite ultrathin Co-based MOFs composite nanosheets for enhancing the antibacterial effect of CDT:In this study,silver peroxide nanoparticles（Ag₂O₂ NPs）were constructed and grown on ZIF-67 nanosheets by in situ oxidation to achieve the successful preparation of ZIF-67@Ag₂O₂nanosheets and then ZIF-67@Ag₂O₂ nanosheets with the ability to self-generate H₂O₂ were triggered by the mildly acidic environment of IME.Lamellar ZIF-67 nanosheets were shown to rapidly degrade and release Co²⁺,allowing conversion of less reactive H₂O₂ into·OH,the most harmful toxic reactive oxygen species（ROS）,for enhanced CDT antibacterial properties.In vivo results revealed that the ZIF-67@Ag₂O₂ nanosheets system exhibits excellent antibacterial performance against both Gram-positive（S.aureus）and Gram-negative（E.coli）bacteria.Therefore,this study presents a promising alternative broad-spectrum antibacterial approach and provides a new therapeutic strategy to achieve an IME-responsive,CDT-mediated and efficient bactericidal platform.（4）Acid-responsive composite nanocatalytic system for ST synergistic enhancement of antibacterial performance of CDT:In this study,acid-responsive MnO₂@Au@ZIF-67 nanoplatform was synthesized using flower-like manganese dioxide（MnO₂）nanoparticles loaded with ultra-small Au NPs,encapsulated acidic response to degradation of ZIF-67 to achieve CDT and ST-based synergistic antibacterial therapy.Under the acidic environment,the outer wrapped ZIF-67decomposes and releases Co²⁺,which can catalyze the production of H₂O₂ with strong oxidative activity·OH to achieve CDT,while MnO₂ can generateO₂ to improve the catalytic efficiency of ultra-small Au NPs like glucose oxidase and enhance the production of gluconic acid and H₂O₂ by ST,thus further accelerating the CDT process.In vitro and in vivo experiments have shown that this mutual reinforcement model based on circulating CDT-ST response can achieve"1+1>2"antibacterial therapeutic effect in the infected microenvironment,which opens a new way to establish a multimodal synergistic therapeutic composite nanocatalytic system.