Synthesis And Tri-modal Imaging（UCL/CT/MR）of Core-shell BaYbF₅:Tm@BaGdF₅:Yb,Tm Nanoparticles

In recent years, the lanthanide-doped nanophosphors have been researched extensively and used for bioimaging because of optical properties, magnetic properties and X-ray absorption. They have unique features and benefits in bioluminescence imaging, photosensitive drug carrier, magnetic resonance imaging, X-ray tomography imaging, etc. when they are applied to the medical field.Computed tomography（CT） and magnetic resonance imaging（MRI） are playing an important role in biological imaging and clinical diagnosis. CT through analysising the information of X-ray attenuation in different tissue penetration by computer, showing a threedimensional simulation of high resolution images. But CT provide limited information in the diagnosis of disease, due to the low resolution ability to soft tissue. However, MRI provide a high quality image of the tissue, and avoiding from ionizing radiation damage on the principle. Although both CT and MRI have many advantages each, the resolution of image which on the cellular level always restrictes their development. This problem can be solved by upconversion luminescence（UCL） imaging through the study of existing theory. There is no a mature contrast agent can combine the three imaging methods UCL, CT and MR with each other. Thus, founding and improving a new contrast agent,so that biological imaging can develop their respective advantages and remedy compensate for its own each, which has become the new focus of development of contrast material.We got the following five points by suming up the relative literature include nanoparticles, UCL application, CT and MR contrast agent and multi-mode imaging:（1） The lanthanide-doped nanophosphors play an important role and have a great potential in many fields.（2） UCL, CT and MR imaging have their pros and cons. If we combine three inspection methods which making up their own shortcomings and deficiencies and breaking through the limitation of the single examination,that will provide better solutions about early diagnosis of the disease for clinical.（3） The lanthanide-doped nanophosphors have excellent upconversion performance, X-ray absorption capacity, magnetic properties, controling surface morphology easily, bio-security and versatility, making it ideal for multi-mode contrast agent.（4）, It can be concluded that the molecular materials combinated by BaYbF₅ and BaGdF₅ could be used for a contrast agent on UCL/CT/MR. The incorporation of Tm³⁺ and Yb³⁺/Tm³⁺ will enhance the upconversion luminescence effect, and make the laser and emission wavelengths of light in the near infrared region.（5） As a substrate core-shell structure nanoparticles are more easily processed to a versatile material than single cluster structure. That makes it more potential for development.Objective: Explore a contrast agent of UCL/CT/MR multi-mode imaging, such as being a superior performance, safe, reliable, and having great potential. It is based on rareearth elements Yb, Gd, Tm and a metal element Ba as the main atomic structure, used of core-shell molecular structure, and has the function of UCL/CT/MR multi-mode imaging. Molecular formula: BaYbF₅:0.5%Tm@BaGdF₅: 20%Yb, 0.5%Tm, which is dsigned. The obtained samples should to be characterized, morphology, cell toxicity, UCL/CT/MR imaging performance and so on.Experimental methods:, Ba Yb F5:0.5%Tm@BaGdF₅:20%Yb, 0.5% Tm nanoparticles were prepared by the classical hydrothermal method. First, BaYbF₅:Tm is synthesized by heating solution of Ba（CF₃COOH）₂, CF₃COOH)₂ and 0.5% Tm（CF₃COOH）₂. Then, synthesis of BaYbF₅:Tm@BaGdF₅:Yb,Tm, is by heating solution of Yb（CF₃COOH）₂, Tm（CF₃COOH）₂, Ba（CF₃COOH）₂ and BaYbF₅:Tm again through the hydrothermal synthesis process. Finally, in the biological safety and compatibility considerations, we wrapped polyethylene glycol（PEG） in the case of the outermost BaYbF₅: Tm@BaGdF₅:Yb,Tm.The nanoparticle samples need to be tested and analyzed on its characterization by transmission electron microscopy（TEM）, X-ray diffraction machine（XRD）, Fourier transform infrared spectroscopy analyzer（FTIR） and upconversion luminescence analyzer. Then the nanoparticle samples should be test in vitro cytotoxicity by MTT assay, and in vivo cytotoxicity analysis conducted by histological analysis. Finally, as a contrast agent, in vivo and in vitro UCL, CT, MRI imaging performance test of the nanoparticle sample is the most important.Results: Through the analysis of morphology and physical properties, that the resulting nanoparticle samples is BaYbF₅:Tm@BaGdF₅:Yb,Tm is sure. It confirmed that the nanoparticle samples has a very low cytotoxicity, and it is almost without causing damage to living tissue, which is its consequence of in vivo and in vitro cytotoxicity experiments. The experimental results of in vitro and in vivo UCL, CT, MRI imaging showed that:（1） The material has excellent performance in fluorescence imaging in vitro, and both the excitation and emission light are near infrared light.（2） The material in vitro CT imaging is superior to commercial contrast agent Iobitridol. However, its in vivo CT imaging features are different from Iobitridol, because it has a unique enhancement mode and metabolic pathway that is nanoparticle contrast agent’s characteristic.（3） The material’s characteristic of in vitro MR imaging is similar to commercial contrast agent Gd-DTPA, and achieved in vivo MR imaging of the material by subcutaneous injection.Discussion: In conclusion, BaYbF₅:Tm@BaGdF₅:Yb,Tm nanoparticle materials are safety and reliable in biology, and it has UCL/CT/MR tri-mode imaging capabilities. And compared with the traditional contrast agents and other structure contrast agent of lanthanide-doped nanomaterials, BaYbF₅:Tm@BaGdF₅:Yb,Tm nanoparticles has several advantages:（1） The nanoparticles composed by a variety of contrast material atom can absorb X-ray multimodal, which improved effection of CT imaging.（2） Core shell structure maked up conversion luminescence efficiency improved. At the same time it laid the foundation for the modification of the surface.（3） the size and shape of the nanoparticle is moderate. That extend the circulation time in vivo, and avoid the large-diameter particle contrast agent on the living body of potential hazards.Although the advantages of this material is very obvious, but there are some places in this study the need for further efforts:（1） The metabolic mechanism of the material is not clear, it need further determine the long-term toxicity of the biological material, to extend the time toxicity tests.（2） The need to find its precise optimum concentration in vivo imaging in a variety of modes, through several different concentrations in vivo experiments and combining literature and theory.In addition to comment on the advantages and disadvantages of the material, we can imagine the material surface modification of various functional groups to form a variety of functional derivatives, which can greatly increase the way for future development and the role of the material.Summary: In this study, BaYbF₅:Tm@BaGdF₅:Yb,Tm nanoparticles ware prepared by hydrothermal method. It can be used as a new UCL/CT/MR multi-mode contrast agent. This contrast material has good effect, long cycle time and low toxicity compared with the traditional contrast. It will play a significant role in the medical field in the future while in further clarify its characteristics.