Doping-and LSPR-Based Modulation Of Acidic Oxygen-Producing Noble Metal Nanozymes And Their Application In Cancer Therapy

The tumor microenvironment(TME)is characterized by hypoxia,weak acidity and mild oxidative stress,of which hypoxia is closely related to cancer cell metastasis and tumor development,and is a major contributor to ineffective treatment.The discovery of the nanozyme offers a new approach to alleviate tumor hypoxia by mimicking the activity of catalase(CAT).It can catalyze high levels of H2O2 in TME to produce O2,alleviating hypoxia to improve the efficacy of oxygen-related therapies and inhibit cancer cell metastasis.However,the CAT-like catalytic activity of the nanozyme is affected by the pH of the environment,especially in acidic TME,where the oxygen production capacity of the nanozyme can be limited or even completely lost.Therefore,the design of a nanozyme with excellent CAT-like catalytic activity in an acidic environment is essential for cancer therapy.Among all nanozyme types,noble metal nanozymes have gained much attention in the field of cancer therapy due to their excellent multi-class enzymatic catalytic activity and unique optical properties.On the one hand,the composition and electronic structure of the noble metal can be altered by doping,and the resulting synergistic and electronic effects can enhance its catalytic activity.On the other hand,the optical properties of the noble metal nanoparticles inherently allow for localized surface plasmon resonance(LSPR)in the presence of excitation light,a process accompanied by localized thermal effects and the generation of hot electrons.These properties are expected to further enhance the catalytic activity of the nanozyme.Based on this,we demonstrate a doping-LSPR coupling strategy to construct super acidity-exempt CAT-like nanozyme for oxygen-dominated synergistic cancer therapeutics.The main research of this thesis is as follows.1.Synthesis of noble metal-like CAT nanozymes.Au nanostars(AuNS)with excellent plasmonic properties were synthesized by seed-mediated growth of surfactants,followed by the deposition of platinum(Pt)atoms on the Au surface using hydrothermal reduction to obtain platinum-AuNS nanostars.Finally,Pt-AuNS was loaded with natural glucose oxidase(GOx)and surface modified with polyethylene glycol(PEG)to improve biocompatibility,resulting in a noble metal nanozyme(Pt-AuNS-GOx)with excellent acidic oxygen production capacity constructed.2.Catalytic activity of Pt-AuNS-GOx was examined.Hydrogen peroxide decomposition experiments show that Pt-AuNS-GOx exhibits excellent CAT-like catalytic activity in the pH range of 4 to 9.Density flooding theory(DFT)calculations demonstrate that this is mainly attributed to the effective reduction of the energy barrier for the decomposition of H2O2 to O2 under acidic conditions due to Pt doping.Meanwhile,a 3-fold increase in the oxygen production rate of Pt-AuNS-GOx was found under NIR light irradiation,and it was verified that the combined photothermal and hot electronic effects induced by LSPR led to the increased catalytic activity.In addition,Pt-AuNS-GOx has been found to possess oxidase-like(OXD)catalytic activity,and LSPR can further enhance its OXD-like enzyme catalytic activity by an order of magnitude to achieve effective consumption of glutathione(GSH),with the ability to achieve tumor oxidative therapy.Moreover,Pt-AuNS-GOx shows that the modified GOx can efficiently consume glucose and can perform a GOx/CAT cascade catalytic reaction,which has the potential to enable tumor starvation therapy.3.In vitro/vivo anti-cancer effect of Pt-AuNS-GOx.Based on the multi-class enzymatic(CAT-like,OXD-like,GOx/CAT cascade catalytic)activity of Pt-AuNS-GOx,it was coincubated with tumor cells(4T1 cells).The results showed that it can down-regulate intracellular energy molecules,deplete GSH and lead to the accumulation of lipid peroxide,and can significantly increase the level of oxidative stress in cancer cells under NIR light conditions to achieve efficient killing of tumour cells,with excellent in vitro anti-cancer performance.The anti-cancer effect of Pt-AuNS-GOx in vivo was investigated by establishing a mouse breast cancer model.The results showed that Pt-AuNS-GOx could achieve large scale apoptotic necrosis of tumor cells by triple therapy(starvation therapy,photothermal therapy and oxidative therapy)synergistically under NIR light conditions,and its efficient oxygen production property could down-regulate hypoxia-inducible factor(HIF-1α)to alleviate hypoxic TME and successfully inhibit cancer cell metastasis.In summary,noble metal nanozymes with ultra-high dual class enzymatic activity(OXDlike and CAT-like enzymatic activity)in acidic environments were obtained by two means,doping and local surface plasmon resonance(LSPR),and further coupled with the natural enzyme GOx to achieve excellent cascade anticancer effects.The research results of this thesis are a guide to the design and development of highly effective noble metal nanozymes,which are expected to achieve highly effective anti-cancer therapy for TME characteristics.