Cooperative Doping in Ultrasmall BaF₂ Nanocrystals for Multimodal ¹⁹F-MRI and CT Applications

Nanostructured metal fluorides (nanofluorides) are an emerging type of inorganic nanocrystals (NCs) with unique physiochemical properties for advanced applications. One recent demonstration used water-dispersed ultrasmall CaF2 nanofluorides as imaging agents that combined the advantages of inorganic NCs with the benefit of background-free 19F-magnetic resonance imaging (19F-MRI). Nevertheless, obtaining small nanofluorides with a face-centered cubic crystal structure, where all fluorides are magnetically equivalent to result in a single 19F NMR signal, is challenging for other types of nanofluorides, preventing their use in 19F-MRI. Here, we show the development of ultrasmall, water-dispersed, barium fluoride (BaF2) NCs for bioimaging applications. By doping BaF2 with two types of lanthanides, diamagnetic-La3+ and paramagnetic-Sm3+, we were able to control the morphology and 19F-MR properties of the final La,Sm:BaF2 (termed LaSamBa) formulation. The fine-tuning of the La3+ content enabled us to obtain monodispersed 4.5 nm NCs, and control over the Sm3+ content provided LaSamBa with very short T1 relaxation properties (ca. 100 ms) needed for enhanced 19F-MRI sensitivity. This type of nanofluorides was examined in two different imaging modalities (i.e., 19F-MRI and CT), benefiting from their single 19F-NMR signal and the high atomic number of barium atoms, respectively. As their 19F chemical shift significantly differs from that of other nanofluorides (e.g., CaF2 and SrF2), LaSamBa expanded the nanofluoride library for future multitarget 19F-MRI studies.