The development of superparamagnetic nanoparticles, such as monocrystalline iron-oxide (MION), has been central to the development of magnetic resonance molecular imaging. Magnetic nanoparticles have been used to label stem cells for tracking, to image tissue macrophage infiltration, and to detect specific and sparsely expressed molecular targets and transgenes. The strong magnetic dipole field generated by these susceptibility agents shifts the resonance frequency of water molecules in the vicinity of the nanoparticle and decreases their relaxation times. These effects lead to a strong and highly detectable decrease in the MRI signal intensity in the vicinity of the nanoparticle on T2-weighted, T2*-weighted, and steady-state free precession (SSFP) images. However, these conventional imaging techniques do suffer from several problems: 1) extremely high local concentrations of MION may produce a complete signal void precluding the accurate quantification of nanoparticle concentration; 2) the detection of MION in regions with low intrinsic signal-to-noise ratio is difficult; 3) it is difficult to distinguish MION induced susceptibility changes from those caused by susceptibility artifacts such as air-tissue interfaces; 4) the long echo times required to detect low concentrations of MION complicate the detection of moving objects, such as the heart, where short echo times are optimal.
We have explored the use of an Off-Resonance Imaging (ORI) technique for generating positive or bright contrast from magnetic nanoparticles to attempt to overcome some of these challenges. We have investigated the sensitivity, specificity and linearity of ORI as a function of both MION concentration as well as magnetic field strength (4.7 and 14 T). MION phantoms with and without an air interface as well as MION uptake in a mouse model of healing myocardial infarction were imaged. MION-induced resonance shifts were shown to increase linearly with MION concentration. In contrast, the ORI signal intensity was highly non-linear, initially increasing with MION concentration until T2 became comparable to the spin-echo time and decreasing thereafter. The specificity of ORI to distinguish MION-induced resonance shifts from on-resonance water was found to decrease with increasing field due to the increased on-resonance water linewidths (15 Hz at 4.7 T versus 45 Hz at 14 T). Large resonance shifts (~300 Hz) were observed at air-tissue interfaces at 4.7 T, both in vitro and in vivo, and lead to poor ORI specificity for MION concentrations less than 150 μg Fe/ml. The in vivo ORI sensitivity was sufficient to detect the accumulation of MION in macrophages infiltrating healing myocardial infarcts, but the specificity was limited by non-specific areas of positive contrast at the air-tissue interfaces of the thoracic wall and the descending aorta. Improved specificity and linearity can, however, be expected at lower fields where decreased on-resonance water linewidths, reduced air-induced resonance shifts and longer T2 relaxation times are observed. The optimal performance of ORI will thus likely be seen at low fields, with moderate MION concentrations and with sequences containing very short echo times.