Application Of Nano Agents With Toxic Free Radicals And Improvement Of Hypoxic Microenvironment In Tumor Therapy

Cancer is one of the most deadly diseases,and the number of its patients is increasing despite the efforts of global experts.There are various traditional treatment methods,such as radiation therapy（radiotherapy）,chemical therapy（chemotherapy）,tumor surgical resection,however,they cannot eradicate tumor.What’s worse,they may even cause adverse reactions.For instance,the increase in the frequency of chemotherapy will produce certain toxicity to the normal tissues of the body and incomplete surgical resection may also lead to the spread and metastasis of cancer cells.Therefore,a well-designed cure program is a matter of great urgency.In recent years,with the rapid development of nanotechnology,nanomaterials,due to its small size,unique optical,magnetic and electrical properties,have manifested its prominent advantages over traditional treatment methods when applied in tumor treatment.Furthermore,low toxicity and good bio-safety are the foundation of inorganic nanomaterials,which play an important role in targeted tumor therapy,phototherapy,chemodynamic therapy（CDT）,sonodynamic therapy（SDT）,enzyme therapy and immunotherapy.In light of the growing attention on the treatment based on inorganic nanomaterials,the focus of current research on the multi-functional inorganic nanomaterials,and multi-modal treatment combined with anti-tumor to completely cure tumors,it is feasible to design and develop new multifunctional inorganic nanomaterials to treat tumors.This thesis focuses on designing multi-functional nano-agents that can alleviate tumor hypoxia microenvironment and promote cell oxidative stress damage and then cooperate with glucose consumption therapy,gas therapy and immunotherapy synergistic anti-tumor.Two kinds of intelligent nano-platforms were constructed using acoustic sensitizer（TiO₂）and photocatalyst(BiO_2-x)as carriers for tumor therapy.First of all,given that ultrasound is a non-invasive external stimulation and can penetrate deep into tumor tissue,and inorganic sound sensitive agent and good bio-safety of TiO₂is the focus of research.Then,the mesoporous TiO₂ nanospheres were synthesized by hydrothermal method,and then Pt nanoparticles were grown in situ on the surface to form platinum-titanium schottky nanoparticles,which not only catalyzed the decomposition of tumor endogenous H₂O₂ to release oxygen for Relieve hypoxia,and the participation of Pt enables the efficient and rapid utilization of Schottky’s electron holes to generate a large amount of reactive oxygen species ROS（e.g.¹O₂and·OH）,causing oxidative stress damage in cancer cells and death.Secondly,cancer cells need to consume a lot of energy because of their rapid growth,Glucose oxidase is used to consume glucose to block the energy supply of cells to curb cell growth.Simultaneously,the electrostatic adsorption of polyethyleneimine on the platinum-titanium schottky junction makes glucose oxidase（GOx）successfully connected to form TiO₂@Pt/GOx（TGP）multifunctional nanomaterial.On the one hand,TGP utilizes the characteristics of high H₂O₂ expression in tumors to release a large amount of oxygen and ROS under the action of ultrasound,which not only consumes intracellelar glucose but also destroys cell redox homeostasis,eventually leading to cell death,exhibiting good anti-tumor effects both in cells and in vivo.On the other hand,TGP has good bio-safety,and also induces strong immunogenic cell death（ICD）,showing outstanding therapeutic effects on the treatment of distal tumor and lung metastasis.In addition,based on its unique enzyme activity advantages,defective BiO_2-x can catalyze H₂O₂ to produce a large amount of oxygen and ROS（e.g.·OH and·O₂^-）in a weak acid environment,thus leading to cell death.At the same time,it combines the unique properties of BiO_2-x to catalyze CO₂reduction of CO under the stimulation of near infrared light in the near infrared wide absorption range.Therefore,the BiO_2-xsynthesized by hydrothermal method was designed and constructed as a carrier,and then a layer of CaCO₃ capsid was coated on its nanosheets by the principle of biomineralization,PEG was modified,and finally BCP(BiO_2-x@CaCO₃/PEG)multifunctional nanomaterial was successfully constructed.The acid-responsive decomposition of BCP in tumors releases CO₂ and Ca²⁺,which is irradiated by near-infrared light and reduces CO₂,thus realizing CO gas therapy.Meanwhile,Ca²⁺is overloaded in cells,leading to mitochondrial dysfunction.To sum up,the multifunctional nano-agent BCP has realized the synergistic treatment of tumor through CO gas therapy,oxygen regulation of hypoxia environment,ROS promoting cellular oxidative stress damage and intracellular Ca²⁺overload.Above all,BCP,due to its biological safety and anti-tumor in vivo,has exhibited excellent clinical application prospect.