Lanthanide-Doped Hafnia Nanoparticles for Multimodal Theranostics: Tailoring the Physicochemical Properties and...

High-Z metal oxide nanoparticles hold promise as imaging probes and radio-enhancers. Hafnium dioxide nanoparticles have recently entered clinical evaluation. Despite promising early clinical findings, the potential of HfO₂ as a matrix for multimodal theranostics is yet to be developed. Here, we investigate the physicochemical properties and the potential of HfO₂-based nanoparticles for multimodal theranostic imaging. Undoped and lanthanide (Eu³⁺, Tb³⁺, and Gd³⁺)-doped HfO₂ nanoparticles were synthesized and functionalized with various moieties including poly(vinylpyrrolidone) (PVP), (3-aminopropyl)triethoxysilane (APTES), and folic acid (FA). We show that different synthesis routes, including direct precipitation, microwave-assisted synthesis, and sol-gel chemistry, allow preparation of hafnium dioxide particles with distinct physicochemical properties. Sol-gel based synthesis allows preparation of uniform nanoparticles with dopant incorporation efficiencies superior to the other two methods. Both luminescence and contrast properties can be tweaked by lanthanide doping. We show that MRI contrast can be unified with radio-enhancement by incorporating lanthanide dopants in the HfO₂ matrix. Importantly, ion leaching from the HfO₂ host matrix in lysosomal-like conditions was minimal. For Gd:HfO₂ nanoparticles, leaching was reduced >10× compared to Gd₂O₃, and no relevant cytotoxic effects have been observed in monocyte-derived macrophages for nanoparticle concentrations up to 250 μg/mL. Chemical surface modification allows further tailoring of the cyto- and hemocompatibility and enables functionalization with molecular targeting entities, which lead to enhanced cellular uptake. Taken together, the present study illustrates the manifold properties of HfO₂-based nanomaterials with prospective clinical utility beyond radio-enhancement.