Application Of Group ?B Oxygen Defective Inorganic Nanomaterials In Tumor Treatment

As a malignant disease with an increasing incidence,cancer has the characteristics of rapid proliferation and division as well as the ability to easily metastasize and relapse,which has always been a common problem faced by researchers from all walks of life.Traditional treatment methods include surgery,chemical drug therapy(chemotherapy),radiation therapy(radiotherapy),etc.Although they have certain therapeutic effects,they can not eradicate tumor cells,but also cause a series of side effects,resulting in damage to normal cells.In recent years,nanomaterials have gradually been used in tumor treatment due to their small size effect and passive targeting ability,and a series of new solutions have been provided for tumor treatment.Among them,inorganic nanomaterials with good biocompatibility,low toxicity and high stability have been favored by many researchers.However,most inorganic nanomaterials with excellent properties are difficult to be excited by safe radiation sources,and are not suitable for in vivo treatment,which limits their application in tumor therapy.As a new type of inorganic nanomaterials,defective inorganic nanomaterials retain the good biocompatibility and stability of the raw materials,while shortening the band gap width and widening the light absorption of the raw materials in the near-infrared region by forming defect sites on the surface of it,breaking the limitations of most traditional inorganic nanomaterials in tumor treatment,and opening up a new direction for nano diagnosis and treatment.In this paper,two kinds of oxygen-deficient inorganic nano-oxides based on homologous elements were innovatively constructed by high temperature reduction method.The former has good biocompatibility and photothermal properties.By functionalized modification on its surface,small molecules with different properties can be connected to achieve the combined treatment of tumors.In order to explore whether the elements of the same family have similar or better performance after oxygen deficiency,we constructed another inorganic nano-oxide of the same family as the former,and targeted small molecules were modified to increase the accumulation in tumor,so as to achieve the purpose of multiple therapy with simple materials.Therefore,the research of this paper is mainly divided into the following two parts:First,sodium borohydride was used as a reducing agent to synthesize oxygen-deficient titanium dioxide nanoparticles(Ti O_2-xNPs)with good NIR-?photothermal effect through high-temperature thermal reduction.Subsequently,Ti O_2-xNPs reacted with 3-aminopropyltriethoxysilane(APTES),and the two were connected by Ti-O-Si bonds.The surface of Ti O_2-xNPs was modified with amino groups,in order to connect the carboxyl group.The photosensitizer chlorin e6(Ce6)was attached to the surface of Ti O_2-xNPs by the amidation reaction,then formed a defect-type titanium dioxide nanocomposite(TAC)loaded with Ce6,which realized the combination therapy of NIR-?photothermal therapy and photodynamic therapy.Later,the successful synthesis of the complex and evaluation of its main properties were verified by dynamic light scattering(DLS),transmission electron microscope(TEM),ultraviolet-visible near-infrared spectrophotometer,X-ray photoelectron spectroscopy(XPS),X-ray diffraction spectroscopy(XRD),thermal imager and other instruments.And the mouse breast cancer cells(4T1)and human cervical cancer cells(Hela)were both used to explore the effect of the nanocomposite on the cell level.The results proved that the nanocomposite could obviously inhibit tumor growth and induce cell apoptosis,and had good biocompatibility to normal cells.Subsequently,a mouse model with 4T1 tumor was constructed,then the nanocomposite was injected into the mouse body through the tail vein and laser treatment was performed,and the mouse body weight and tumor size were weighed daily to evaluate the therapeutic effect of the nanocomposite in vivo.As a result,it was found that the tumor growth after treatment with the nanocomposite was significantly inhibited,which proved that the nanocomposite TAC combined with external laser stimulation had a good tumor inhibitory effect.In order to investigate the properties of other?B group anoxic-inorganic nano-oxides,magnesium powder was used as a reducing agent to synthesize a kind of defective zirconium dioxide nanoparticles(Zr O_2-xNPs).By modifying the surface of Zr O_2-xNPs with polyethylene glycol(PEG),the dispersibility and blood circulation time of NPs were increased under physiological conditions.Subsequently,the penetrating peptide(c RGD)was connected with PEG to modify it on the surface of Zr O_2-xNPs,and the c RGD-loaded defective zirconium dioxide nanocomposites(ZPR NPs)were obtained.Among them,c RGD,as a polypeptide molecule,can specifically bind to the highly expressed integrin?_v?₃on the tumor cell membrane,and actively target the tumor site.The obtained Zr O_2-xNPs has strong light absorption in NIR-?,can be used for photothermal therapy of tumor cells.In addition,the shortening of the band gap caused by the defect enhanced the electron-hole pair separation effect of Zr O_2-xNPs,thereby generating a large amount of ROS,which has a good sonodynamic effect.Interestingly,the high temperature and ROS generated by photothermal therapy and sonodynamic can destroy tumor cell structure and homeostasis while simultaneously inducing immunogenic cell death(ICD),releasing damage-related molecular patterns(DAMPs),and enhancing the activity of the antigen presentation cells,which can activate cytotoxic T cells and secrete immune cytokines to achieve the purpose of initial activation of the immune system and the effect of immunotherapy.Through in vivo and in vitro experiments,it is proved that ZPR NPs can indeed achieve the effect of sonodynamic combined immunotherapy with NIR-?photothermal sensitization.Compared with TAC,ZPR not only has the ability of active targeting to increase the accumulation and retention of nanoparticles in tumor sites,but also has stronger tissue penetration with its NIR-photothermal and sonodynamic properties,which is more suitable for the elimination of deep tumors.Through in vitro characterization and cell experiments,it was found that ZPR NPs can achieve good damage to tumor cells with less laser and ultrasound power,and further reduce the possibility of damage to normal tissues caused by external stimuli.After establishing the mouse tumor model,the experimental results also proved that ZPR NPs can achieve better tumor ablation effects in vivo.