Disruptive chemical doping in a ferritin-based iron oxide nanoparticle to decrease r₂ and enhance detection with T₁-weighted MRI

Inorganic doping was used to create flexible, paramagnetic nanoparticle contrast agents for in vivo molecular magnetic resonance imaging (MRI) with low transverse relaxivity (r₂). Most nanoparticle contrast agents formed from superparamagnetic metal oxides are developed with high r₂. While sensitive, they can have limited in vivo detection due to a number of constraints with T₂ or T₂*-weighted imaging. T₁-weighted imaging is often preferred for molecular MRI, but most T₁-shortening agents are small chelates with low metal payload or are nanoparticles that also shorten T₂ and limit the range of concentrations detectable with T₁-weighting. Here we used tungsten and iron deposition to form doped iron oxide crystals inside the apoferritin cavity to form a WFe nanoparticle with a disordered crystal and un-coupled atomic magnetic moments. The atomic magnetic moments were thus localized, resulting in a principally paramagnetic nanoparticle. The WFe nanoparticles had no coercivity or saturation magnetization at 5 K and sweeping up to ±20 000 Oe, while native ferritin had a coercivity of 3000 Oe and saturation at ±20 000 Oe. This tungsten-iron crystal paramagnetism resulted in an increased WFe particle longitudinal relaxivity (r₁) of 4870 mm^-1 s^-1 and a reduced transverse relaxivity (r₂) of 9076 mm^-1 s^-1 compared with native ferritin. The accumulation of the particles was detected with T₁-weighted MRI in concentrations from 20 to 400 nm in vivo, both injected in the rat brain and targeted to the rat kidney glomerulus. The WFe apoferritin nanoparticles were not cytotoxic up to 700 nm particle concentrations, making them potentially important for targeted molecular MRI.