Size and Zinc Substitution Govern the MPI and MRI Performance of Ferrite Nanoparticle Tracers

Abstract Magnetic nanoparticles (MNPs) that can support both magnetic particle imaging (MPI) and magnetic resonance imaging (MRI) are attractive for dual-modal imaging because they combine the quantitative, background-free tracer detection of MPI with the anatomical contrast of MRI. However, the MPI- and MRI-relevant performance of ferrite nanoparticles is strongly governed by core size, composition, magnetic relaxation, and biological environment. Here, we report a comparative study of four lab-synthesized, quasi-cubic MNP formulations: 30 nm Fe3O4 nanoparticles (F1), 10 nm Fe3O4 nanoparticles (F2), 30 nm Zn0.4Fe2.6O4 nanoparticles (Z1), and 10 nm Zn0.4Fe2.6O4 nanoparticles (Z2). The morphological, physicochemical, cytocompatibility, and cellular uptake properties of these nanoparticles were systematically characterized. Magnetic particle spectroscopy (MPS) was used as an MPI-relevant screening method to compare the dynamic magnetization responses of these nanoparticles under excitation fields in both water and agar phantoms. Z1 produced the strongest mass-normalized harmonic amplitudes under 7.75 kHz excitation in both water and agar phantoms, identifying it as the highest signal formulation for MPI applications. Agar embedding generally reduced the harmonic amplitudes, consistent with restriction of Brownian rotation and demonstrating that physical confinement can strongly affect the MPI-relevant tracer response. Among the 10 nm formulations, Z2 generated stronger absolute harmonic signals than F2 under both conditions and produced the second-highest harmonic amplitudes in the agar phantom. T1-weighted MRI phantom imaging further confirmed concentration-dependent signal attenuation. Z2 and F2 generated more localized hypointense contrast under T1-weighted imaging conditions, while Z1 and F1 generated susceptibility-related signal loss extending beyond the physical boundaries of the inclusions at equivalent nanoparticle concentrations. This spatially extended hypointensity can obscure boundary definition and complicate quantitative signal-intensity analysis. Overall, these findings clarify how core size and Zn substitution regulate the magnetic, biological, MPI-relevant, and MRI-relevant behavior of ferrite nanoparticles and identify Z2 as a promising balanced tracer candidate for dual-modal MPI-MRI imaging.