Iridium Ruthenium Alloy/Iridium Oxide Bionic Nanoenzyme Enhances Oxidation Therapy And Cooperates With Starvation Therapy/Photothermal Therapy For Breast Cancer Treatment

Cancer has become a serious threat to human health.It is a long-term goal to explore and study effective treatment strategies.The discovery of nano enzyme provides a new method and method for the treatment of tumor,and attracts the research interest of the scientific community.In 2007,it was first found that Fe₃O₄ nanomaterials have the catalytic properties similar to horseradish peroxidase.At present,it has been able to design and synthesize ideal nanomaterials to simulate the catalytic properties of enzyme.The unique physical and chemical properties of nano enzyme at the nano level,such as ultra-small particle/side size,high stability,adjustable catalytic activity,large surface area,multiple functions and sensitive response to external stimulation,make it have excellent catalytic performance,and have important applications in many fields,such as biomedical applications,providing a new strategy for the treatment of a variety of diseases.It is worth mentioning that nano enzyme has shown good effect in the treatment of a variety of tumor diseases,and has successfully developed a variety of types of nano enzyme for the diagnosis and treatment of cancer.However,there are still some problems to be solved in this field.（1）The current development of nano enzymes for cancer treatment mainly mimics oxidoreductase,namely peroxidase and catalase.These nano enzymes used in cancer therapeutics are mainly limited to a few inorganic catalysts（Fe₃O₄,Mn O₂,etc.）,and there are few kinds,so more kinds of nano enzyme materials need to be found or developed.（2）The activities of natural enzymes are strictly regulated in the biological system,which provides us with strategies to regulate the activities of nano enzymes.It is necessary to control its surrounding environment and its interaction with specific ligands to achieve the catalytic activity of nano enzyme,that is,it has the same biological response as natural enzyme.（3）In order to achieve higher catalytic performance and be used in tumor imaging and treatment,it is necessary to use appropriate coating to achieve the perfect balance between the ideal targeting ability and high catalytic activity.（4）The biological safety of in vivo treatment.Based on the above background,by adjusting the size,surface modification and composition of nano enzyme,we can synthesize high-efficiency nano enzyme with tumor specificity,better permeability and biocompatibility.Finally,it can be combined with natural enzymes or nano materials,which is more conducive to the treatment of solid tumors.Chapter 1:The introduction briefly describes the concept and research progress of nano enzyme,briefly introduces the types of nano enzyme,then summarizes and analyzes various regulatory factors of nano enzyme,and finally focuses on the application and progress of nano enzyme in the field of tumor.Chapter 2:We use a simple method to synthesize ultra-small iridium-ruthenium alloy nanoparticles（Ir Ru NPs）with dual enzyme activity,and perform PEG surface functionalization to improve the biocompatibility of the nanoparticles.At the same time,loaded with natural glucose oxidase（GOx）,a multi-enzyme active nano-enzyme system Ir Ru-GOx@PEG NPs that can cascade catalytic reactions was constructed.In the first catalytic stage,GOx in Ir Ru-GOx@PEG NPs degrades the sensitive glucose of tumor tissue into hydrogen peroxide（H₂O₂）,cuts off the nutritional source of the tumor,and inhibits tumor growth through starvation therapy.In the second catalytic stage,Ir Ru NPs in Ir Ru-GOx@PEG NPs convert upstream endogenous H2O2into highly toxic ¹O₂ and O₂,of which ¹O₂ can directly induce tumor cell apoptosis through oxidation therapy,while O₂ solves Hypoxia in the environment leads to the termination of the response to starvation therapy,so that the response cycle of starvation therapy continues to occur,and it also inhibits tumor metastasis caused by hypoxia.We first verify that Ir Ru-GOx@PEG NPs has good and stable catalytic performance through in vitro catalytic activity experiments Cell death test proved that it can effectively induce apoptosis of 4T1 cancer cells.In addition,the in vivo results further prove that Ir Ru-GOx@PEG NPs can cooperate with starvation therapy and oxidation therapy to effectively treat breast cancer.This treatment strategy is expected to be used in the treatment of other cancers and bring new treatment strategies for cancer treatment.Chapter 3:Photodynamic therapy（PDT）of tumors has achieved good results,but due to the lack of effective photosensitizers and tumor hypoxia problems,its treatment efficiency is not high.In this study,we synthesized Ir O₂ NPs with excellent photothermal/photodynamic effects and catalase-like activity by a simple method.Hyaluronic acid（HA）combines the enzyme activity of glucose oxidase（GOx）with the catalase activity of Ir O₂ NPs（Ir O₂-GOx@HA NPs）to target the tumor site,forming an in situ amplifier in the tumor microenvironment（In-situ magnifier abbreviation ISM）.That is,GOx first converts high levels of glucose in the tumor to hydrogen peroxide（H₂O₂）,and then uses the catalase activity of Ir O₂ NPs to convert H₂O₂ to O₂.This caused the tumor microenvironment to change from hypoxia to increased O₂ content,thereby enhancing PDT.The excellent photodynamic performance of Ir O₂ NPs has been confirmed,which mediates the type II photodynamic mechanism.Ir O₂ NPs with high photothermal conversion efficiency have stable photothermal properties and can also be used as a photosensitizer for photothermal therapy（PPT）.In addition,Ir O₂ NPs can effectively catalyze the generation of oxygen from H₂O₂ and exhibit better catalase-like activity.In cancer cells,the intensity of ROS generated by the photodynamic effect mediated by Ir O₂-GOx@HA NPs is much higher than that of Ir O₂ NPs alone,indicating that the amplifier can be effectively implemented in the cell as envisaged.Ir O₂-GOx@HA NPs-mediated amplifier enhances the effect of type II PDT,aggravates the apoptosis of breast cancer（4T1）cells,and cooperates with its own PPT to further improve the overall treatment effect.Under simulated hypoxic conditions of tumor tissue,it was found that Ir O₂-GOx@HA NPs treatment can effectively relieve hypoxia inside tumor tissue.This strategy of using GOx and Ir O₂ NPs to form an enzyme in-situ amplifier to in turn enhance its own PDT effectively solves the reduction in the treatment efficiency caused by hypoxia.The strategy of using nanozymes to solve the limitations of conventional treatment methods can also be applied to other disease treatments to improve the treatment effect,and is very promising.