Research On Preparation,Surface Modification And In Vivo PET/CT Imaging Of Near Infrared Light-driven Nano-Photosensitizers

Cancer is a common and fatal disease that seriously endanger human health at present.Diagnosis and treatment of cancer has always been one of the most important topics in clinical medicine.Imaging technology is an indispensable method to obtain the location of tumor and evaluate the formation and development of tumor.Accurate identification of tumor is very important to improve the cure rate of cancer.Surgical treatment,radiotherapy and chemotherapy are the main methods for clinical treatment of cancer nowdays,but the therapeutic effect of cancer remained unsatisfactory due to many factors including the seriously toxic and side effects,limited curative effect,multidrug resistance,invalidity in metastatic tumor,etc.Photodynamic therapy?PDT?is a method of producing local oxidation under light irradiation to cause lethal damage and tumor necrosis.Compared with chemotherapy and radiotherapy,PDT has many unique advantages,including high degree of localization,negligible injury,high specificity,good safety and economy,etc.However,the main disadvantages of clinical PDT is poor therapeutic effect on tumors with large size or those enclosed in deep tissues due to the limited penetration depth in the tissue of the visible light or ultraviolet light used to excite the photosensitizer,which is contributed to the light absorption and scattering of the biological tissue.Rare earth-doped upconversion luminescent nanomaterial?UCN?is capable to absorb photons with long wavelength to emit short-wavelength photons.When UCN combined with a photosensitizer are excited by near-infrared light?NIR?,the upconversion luminescence at ultraviolet and visible region can excite the photosensitizer to produce the reactive oxygen species?ROS?,which can kill cancer cells.These strategies overcome the shortcoming of current PDT.In addition,UCN composites can be used as MRI or CT contrast agents as well as multimodal imaging probes by virtue of the optical and magnetic properties of rare earth ions.In this dissertation,UCN@TiO₂-Au,a nanocomposite with multimodal imaging and photodynamic therapeutic properties was constructed.The effect of surface modification strategy of the material on the application performance of its products was studied.Two kinds of targeted nano-photosensitizers are prepared by coupling UCN@TiO₂-Au with different ligands through the preferred modification method.The PET/CT imaging performance of ¹⁸F-labeled targeted nano-photosensitizers was investigated in mice tumor model.The specific research contents and results are as follows:?1?NaYF₄:Yb,Tm@NaGdF₄:Yb nanoparticles?UCN?were prepared by solvothermal method,then coated with TiO₂ by hydrolysis method and followed by deposition of Au grains by photochemical method to prepare the nano-photosensitizer UCN@TiO₂-Au.Effects of illumination time and the dosage of chloroauric acid on the morphology,luminescence intensity and ROS generation capacity of UCN@TiO₂-Au were studied.The feasibility of the nano-photosensitizer for MRI and CT contrast agents was evaluated by in vitro MRI and CT tests.Two method based on different strategies was used to modify UCN@TiO₂-Au with polyethylene glycol?PEG?.One is the silane coupling agent method widely used in the current documents,and another is the Au-S assembly method presented here.The zeta potential,luminous intensity,dispersion stability and ROS generation capacity of the obtained PEG-modified UCN@TiO₂-Au were characterized.The results proved that the products prepared by the modification method via Au-S assembly chemistry have better application properties.?2?With the aid of Au-S assembly chemical method,two ligands with different tumor targeting functions,folic acid?FA?and arginine-glycine-aspartic acid cyclic peptide?RGD?,were respectively coupled to UCN@TiO₂-Au to fabricate tumor-targeted nano-photosensitizers.The chemical composition,zeta potential,up-conversion luminescence,labeling efficiency for radioactive ¹⁸F^-ions and dispersion stability of the targeted nano-photosensitizers were characterized.The in vivo imaging performance of ¹⁸F-labeled targeted nano-photosensitizers was studied in mice tumor model by using positron emission computed tomography/electronic computer X-ray tomography?PET/CT?.The results confirmed the feasibility of the nano-photosensitizers for in vivo PET/CT imaging and the targeting effect for tumor.It is expected to serve as a theranostic nanoplatform for photodynamic therapy and multimodal imaging.