Design Of Soft X-ray Triggered Rare Earth Fluoride Nanoprobe,Regulation Of Optical Properties And Application In Gas Therapy

The design of soft X-ray activated rare-earth fluoride nanomaterials,the regulation of optical properties and the application for gas therapy have attracted much attention.However,most developed lanthanide doped nanomaterials are triggered by ultraviolet(UV)or near-infrared(NIR)light.Due to the large absorption and scattering of photons in tissues,lanthanide doped nanomaterials activated by traditional light sources(UV/Visible/NIR)are limited by shallow penetration depth,resulting in low detection sensitivity and low efficiency.Compared with UV light and NIR light,X-ray irradiation with the advantage of unlimited penetration depth,can be used as a new generation of excitation source for deep tissue biological imaging and anti-tumor treatment.Moreover,some nanomaterials with high atomic number(Z)(named as scintillators)can be used as photo-transducer for converting soft X-ray radiation into UV,visible or NIR emission.Fortunately,lanthanide scintillators with large X-ray absorption efficiency not only possess the excellent down-shifting/upconversion(UC)emission,but also present outstanding radioluminescence,which are emerged as new typed agents for X-ray-excited fluorescence(XEF)imaging.Due to the complexity,diversity,heterogeneity and easy metastasis of tumors,cancer is one of the most difficult diseases to be treated in the world.Therefore,effective treatment of cancer is still an important problem to be solved urgently at present.At present,traditional treatment is widely used in cancer treatment,including radiotherapy,surgery and chemotherapy,but they all suffer from inevitable defects.In recent years,with the rapid development of nanomedicine,some new cancer treatment methods have been development,such as photodynamic therapy,gas therapy.Compared with the traditional therapeutic methods,these new therapeutic methods have the advantages of fewer side effects,better therapeutic effect and better selectivity.However,there are still many problems in tumor treatment,such as low penetration depth of excitation light source,low efficacy of single therapy,and low efficacy of deep tissue therapy.In order to overcome these problems,in this thesis,we aim to construct multi-functional soft X-ray activated rare-earth fluoride nanomaterials to improve the penetration depth of excitation light and the treatment efficiency.The main contents of this thesis are listed as follows:(1)Based on the fluorescence resonance energy transfer,low dose soft X-ray responsive NaYF₄:Gd/Tb@SiO₂@RBS gas delivery nanoplatform was designed by integrating NaYF₄:Gd/Tb scintillation nanorods with light-controlled NO gas release molecule[NH₄][Fe₄S₃(NO)₇](Roussin's Black Salt,RBS).Due to the excellent X-ray triggered green fluorescence emission,the controlled release of NO gas was successfully achieved,and the continuous NO release triggered by soft X-ray in deep tissue(about 3 cm)was realized.The results of in vitro cell and in vivo tumor therapy reveal that the nanoprobe has excellent gas therapy efficiency under low dose soft X-ray excitation.Therefore,the soft X-ray activated nanoplatform for NO release provides a promising gas therapy model for the treatment of deep-tissue cancers in the future.(2)Basedon NaLuF₄:Gd/Tbnanoparticles,NaLuF₄:Gd/Tb@NaLuF₄@mSiO₂ core-shell nanocomposites were successfully prepared,which improves the radioluminescence intensity(about 1-fold)triggered by soft X-ray because of inhibiting the surface quenching effect.Soft X-ray excited NaLuF₄:Gd/Tb@NaLuF₄-RBS gas deliverer was further constructed by loading NO donor(RBS).And,the controlled release of NO was achieved for inhibition of tumor growth.(3)The in-situ growth strategy of PAA surface modification was developed to synthesize NaLuF₄:Gd/Tb@MOF nanocomposite structure.Based on fluorescence resonance energy transfer,NaLuF₄:Gd/Tb@MOF+L-arginine photodynamic/gas multi-modal synergistic treatment platform was constructed by loading L-arginine.Deep tissue photodynamic therapy triggered by soft X-ray and ROS induced NO release have been realized,providing a new combination therapy strategy triggered by soft X-ray for tumor treatment.(4)Based on rare-earth fluoride nanoscintillator,NaLuF₄:Ce@TiO₂-L-arginine multifunctional therapeutic probe was constructed by combination of inorganic TiO₂ semiconductor photosensitizer and L-arginine.Under X-ray excitation,NaLuF₄:Ce@TiO₂ can effectively catalyze water to produce ROS.And the generated ROS can further oxidize L-arginine to produce NO,finally leading to synergistic ROS/NO anti-tumor therapy.