Sub-10 nm Water-Dispersible β-NaGdF4:X% Eu3+ Nanoparticles with Enhanced Biocompatibility for in Vivo X-ray Luminescence Computed Tomography.

As a novel molecular and functional imaging modality, X-ray luminescence computed tomography (XLCT) has shown its potentials in biomedical and preclinic applications. However, there are still some limitations of X-ray-excited luminescent materials, such as low luminescence efficiency, poor biocompatibility, and cytotoxicity, making in vivo XLCT imaging quite challenging. In this study, for the very first time, we present on using sub-10 nm β-NaGdF4:X% Eu3+ nanoparticles with poly(acrylic acid) (PAA) surface modification, which demonstrate outstanding luminescence efficiency, uniform size distribution, water dispersity, and biosafety, as the luminescent probes for in vivo XLCT application. The pure hexagonal phase (β-) NaGdF4 has been successfully synthesized and characterized by X-ray powder diffraction (XRD) and transmission electron microscopy (TEM), and then the results of X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectrometry  (EDX), and elemental mapping further confirm Eu3+ ions doped into NaGdF4 host. Under X-ray excitation, the β-NaGdF4 nanoparticles with a doping level of 15% Eu3+ exhibited the most efficient luminescence intensity. Notably, the doping level of Eu3+ has no effect on the crystal phase and morphology of the NaGdF4-based host. Afterward, β-NaGdF4:15% Eu3+ nanoparticles were modified with PAA to enhance the water dispersity and biocompatibility. The compatibility of in vivo XLCT imaging using such nanoparticles was systematically studied via in vitro cytotoxicity, physical phantom, and in vivo imaging experiments. The ultralow cytotoxicity of PAA-modified nanoparticles, which is confirmed by over 80% cell viability of SH-SY5Y cells when treated by high nanoparticle concentration of 200 μg/mL, overcome the major obstacle for in vivo application. In addition, the high luminescence intensity of PAA-modified nanoparticles enables the location error of in vivo XLCT imaging less than 2 mm, which is comparable to that using commercially available bulk material Y2O3:15% Eu3+. The proposed nanoparticles promote XLCT research into an in vivo stage. Further modification of these nanoparticles with biofunctional molecules could enable the potential of targeting XLCT imaging.