Sensitive detection of extremely small iron oxide nanoparticles in living mice using MP2RAGE with advanced image co-registration

Abstract

Magnetic resonance imaging (MRI) is a widely used non-invasive methodology for both preclinical and clinical studies. However, MRI lacks molecular specificity. Molecular contrast agents for MRI would be highly beneficial for detecting specific pathological lesions and quantitatively evaluating therapeutic efficacy in vivo. In this study, an optimized Magnetization Prepared—RApid Gradient Echo (MP-RAGE) with 2 inversion times called MP2RAGE combined with advanced image co-registration is presented as an effective non-invasive methodology to quantitatively detect T1 MR contrast agents. The optimized MP2RAGE produced high quality in vivo mouse brain T1 (or R1 = 1/T1) map with high spatial resolution, 160 × 160 × 160 µm3 voxel at 9.4 T. Test–retest signal to noise was > 20 for most voxels. Extremely small iron oxide nanoparticles (ESIONPs) having 3 nm core size and 11 nm hydrodynamic radius after polyethylene glycol (PEG) coating were intracranially injected into mouse brain and detected as a proof-of-concept. Two independent MP2RAGE MR scans were performed pre- and post-injection of ESIONPs followed by advanced image co-registration. The comparison of two T1 (or R1) maps after image co-registration provided precise and quantitative assessment of the effects of the injected ESIONPs at each voxel. The proposed MR protocol has potential for future use in the detection of T1 molecular contrast agents.

Digital Simulation Assessments of the Sensitivity of Quantitative MRI for Detection of an Iron Oxide Nanoparticle Brain MRI Contrast Agent

“…It is readily apparent that higher relaxivity contrast agents will be more easily detectible. In our previous report 41 we predicted that the lower limit of sensitivity of MP2RAGE derived R1 maps to 3 nm IONP would be 0.03 mM. In the previous report, Kim et al, 2021, 41 , the 3 nm IONPs were intracranially injected into the mouse brain at 2 relatively high concentrations, 0.1 mM and 0.25 mM (Supplementary Fig.…”

“…In this study, the reproducibility was quantitatively presented using absolute difference maps at a voxel-by-voxel level. Alternatively, the testretest signal to noise ratio (TrTSNR) is also applicable to provide quantitative reproducibility of these imaging methodologies as in our previous report 41 . Thus, reporting the voxel-by-voxel reproducibility of the MR methodology for all MR based biomarker studies is recommended.…”

“…In vivo mouse brain R1 maps were obtained at both 4.7 T and 9.4 T, with ve mice each per scanner (Supplementary Fig. 1a -j) The ve mice scanned at 9.4 T were the same subjects from our previous report 41 . Region of interest (ROI) analysis was performed on dorsal cortex, and the quanti ed R1 values were 0.62 ± 0.01 s -1 (4.7 T, n = 5, mean ± standard deviation) and 0.53 ± 0.01 s -1 (9.4 T, n = 5, mean ± standard deviation).…”

“…C57BL6 female mice at 10 weeks of age were purchased from Jackson labs and used at 12-weeks of age. A total 11 mice were used in this study, ve mice at 4.7 T and six mice at 9.4 T. Among the 6 mice scanned at 9.4 T, ve mice, (mouse ID 06-10), were from our previous report 41 .…”

“…The MP2RAGE imaging parameters were TR/TE/TI1/TI2 (ms) = 8000/3/1300/3600, 9-degree ip angle, and 640 ms segment duration with 2 inversion for a k-space plane. The MR protocol of MP2RAGE at 9.4 T is the same as our previous report 41 . The T1 maps of in vivo mouse brain was estimated from raw MP2RAGE and converted into R1 maps.…”