Multi-function On Rare Earth Conversion Luminescent Nano Materials Used In Vivo Imaging Studies

Rare-earth nanoparticles show unique upconversion luminescence (UCL) emission under continuous-wave excitation at980nm, with superior photostability, high signal to noise ratio (SNR) and excellent imaging depth in vivo. But the rare-earth upconversion nanophosphors was still limited by low quantum yields with insufficient UCL intensity. Moreover, UCL imaging was also limited by low resolution and sensitivity in the whole body imaging, and could not be used in quantification imaging and imaging of large animal. Furthermore, the rare earth is not the essential component of human, so the safe injection dose must be carefully assessed. This thesis is focused on these projects and composed of three parts.1. Multifunctionalization of rare earth upconvertion nanophosphors and its bioapplicationswe prepared a NaLuF4based UCNP for tri-modal imaging. NaLuF4based UCNP enhanced the UCL quantum yields into0.67±0.07%and realize lymphatic vessel imaging under ambient light with high SNR. And as a CT contrast, a cit-UCNPs preparation of concentration1mg/mL was equivalent in X-ray absorption to a1.55mg/mL commercial Iopromide injection solution. Furthermore, we successfully demonstrated a lymphatic vessel by CT imaging. For quantification imaging, radiotracer153Sm was post-labeled onto the particles with high yield (>99%) and stability (>99%) only by1min shaking, in vivo stability of the post-labeling was also test and then the particles was used for quantification tracking its pharmakinetics.PEGylated rare earth upconvertion nanophosphors labeled by153Sm was applied in passive tumor targeting imaging.12hours after injection, obvious signal was detected in the tumor and the signal arrive at its peak at36th hour.18F-labeling of upconvertion nanophosphors was achieved efficiently in water at room temperature with an18F-labeling yield of>90%and completed within5min, with only simple purification by aqueous washing and centrifugation, and without the use of organic agents. The labeling was stable in vivo and further applied in lymph monitoring.A core-shell upconvertion nanophosphor, NaLuF4:Yb,Tm@NaGdF4, was mainly designed to improve the MR imaging ability of upconversion nanophosphors without damage of its ability as UCL and X-ray CT probe. And then the particles were post-labeled by18F or153Sm to realize five modal imaging for more information from different sides.2. Rare earth upconvertion nanophosphors as in vivo metastasis tracking agentsA novel NaYF4:Yb,Tm@NLuF4core-shell upconversion nanophosphor with ultra bright upconversion luminescence was synthesized as tracking agents for visualization of choriocarcinoma metastasis.21days after intravenously injection, JEG-3cells was found in the lung and formed tumor nodules. No obvious side effects are detected at the concentration of cell labeling, including cell viability, tumorigenesis and metastasis ability no matter in vitro and in vivo.3. Toxicity of rare earth upconversion nanophosphorsAfter i. v. injection, cit-UCNP were found mostly in the liver and spleen, and little in the lung and kidney. In pregnant mouse, cit-UCNPs was also found in the placenta, while no detectable signal in the offspring. cit-UCNPs was excreted by bile other than urine.200, and20mg/kg wt was found toxic and have obvious side effects. But for the dose of4mg/kt wt, no detectable toxicity was found and the dose was considered as safety dose. After taking an overdose, the synthesis of protein and enzyme suffered an obvious damage. And the bile duct was proved to be blocked. Moreover, the liver cells were destructed seriously, such as disappearance of mitochondria and glycogen. In the lung, serous fluid and leaked red blood cells was found in the alveolus. The particles also induced a Glomerular proliferation. Furthermore, the testicle was detected with obvious signal of particles, and the sperm was damaged, such as changed membrane and decreasing mitochondria.Overdose would significantly decreased the chance of conception and the offspring number but showed no influences on the weight and livability. Offspring showed no obvious variation, and could breed next generation.