The feasibility of NaGdF4 nanoparticles as an x-ray fluorescence computed tomography imaging probe for the liver and lungs.

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As a novel imaging modality, x-ray fluorescence computed tomography (XFCT) can provide distribution and concentration information of contrast agents containing high atomic number elements, such as iodine, gadolinium, barium, gold, and platinum. Since XFCT has a better sensitivity and detection limit of high-Z elements compared with traditional and spectral CT, it becomes a powerful quantitative imaging tool for biological studies. The main problem of current XFCT imaging is its low emission and detection efficiency of x-ray fluorescence (XRF) photons. Increasing XRF photons generation by choosing a high atomic element as a contrast agent is essential to improve the imaging quality of XFCT. Gadolinium emits at least a few times more of XRF photons than gold under the same x-ray excitation condition, leading to a detection limit at a level of sub-mg/mL as the next generation of clinical imaging modality. However, most current XFCT studies have utilized gadolinium salt as the contrast agent, which could not accumulate in organs or tumors efficiently, making in vivo XFCT imaging quite difficult. In this study, we present NaGdF4 nanoparticles with ultra-small size as nanoprobes to test the feasibility for in vivo XFCT application for the first time. NaGdF4 nanoparticles with different sizes (3-10nm) were successfully synthesized via a coprecipitation process by controlling the reaction time at temperature of 290 °C. The morphology, crystal phase, chemical composition, and size of such NPs were further characterized with HR-TEM, XRD, and EDX. The abilities of XRF photons from different sizes of NPs were quantified by our customized XFCT imaging system. To access the in vivo application of as-synthesized NPs, such hydrophobic NPs capped OA molecules were further modified with AEP via a ligand-exchange process and characterized with FT-IR. For in vivo XFCT imaging, 0.1mL of 30mg/mL NPs were injected into nude mice via the tail vein. The Varian G-297 x-ray tube was set to 150kV and 0.5mA. The XRF photons were captured by a Kromek eV-3500 photon counting detector at each 8° for 10s. The successfully synthesized NaGdF4 nanoparticles (3-10nm) were monodisperse, highly uniform spherical morphology and hexagonal crystalline phases. No significant influence on XRF photons yields or XFCT imaging quality were found by varying the nanoparticle size. The XRF photons were 2.5 times more emitted from NaGdF4 nanoparticles (NPs) compared to gold nanoparticles, thereby leading to a better image quality. With the AEP surface modification, such NPs were readily adapted for use in in vivo XFCT applications with monodispersity in aqueous solution and negligible cytotoxicity. With the tail-vein injection, the liver, spleen, and lungs could be clearly imaged with XFCT at a sub-mg/mL level. Such NaGdF4 NPs, which were synthesized with coprecipitation process, were modified with AEP for in vivo XFCT applications. With both the phantom and in vivo experiments, such NPs were proved to be appropriate probes for XFCT application with the detection limit at a sub-mg/mL level. In the future research, such NPs could be further functionalized with targeting molecules for early-phase cancer detection.