Characterizing Iron Oxide NanoParticles using 4D Spectroscopic SWIFT
Jinjin Zhang1, Hattie L. Ring1, Michael Garwood1, and Djaudat Idiyatullin1

1Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States

Synopsis

The ability to accurately and sensitively quantify the bio-distribution of iron oxide nanoparticles is essential for their use as both diagnostic and therapeutic agents in theranostics. In this study, a 4D spectroscopic SWIFT technique was applied and optimized to characterize the distribution of IONPs in mouse invivo up to high concentration (>1.0 mg Fe/g of tissue). The frequency shift due to susceptibility variation and T2* shortening (down to 20 μs) caused by IONPs were detected in mice organs depositing IONPs. The acquired T2* map which provide quantitative information about IONP bio-distribution makes the 4D spectroscopic SWIFT a promising tool in nanoparticle-based theranostics.

Purpose

To investigate the use of 4D spectroscopic SWIFT [1] for invivo assessment and quantification of IONP bio-distribution, and to compare it with the previously reported longitudinal relaxation time constant (T1) assessment in mice.

Introduction

Iron oxide nanoparticles (IONPs) are receiving increased attention for their potential application in theranostics (act as both diagnostic and therapeutic agents) [2]. A noninvasive and quantitative imaging techniques for the assessment of IONP bio-distribution invivo is crucial for effective and safe treatment. To expand the detectable range to clinically relevant levels, which falls into the gap between conventional MRI and CT [3], we have suggested a positive-contrast based technique using SWIFT Look-Locker T1 mapping method [3-5]. However, cell internalization of IONPs will usually influence the relaxivity r1. It has been reported the influence on r2 and susceptibility is much less significant [6]. Therefore, for more accurate assessment and quantification, in supplement to the previous reported T1 technique, a 4D spectroscopic SWIFT technique [1] was applied to characterize IONPs in mice invivo up to high concentration.

Methods and materials

Spectroscopic SWIFT is based on the concept of adding a pseudo gradient to x, y, z gradients, to create an intrinsic spectroscopic frequency distribution [7]. Ideally, to reconstruct a 4D image, we must collect a set of projections with orientations isotropically distributed on a “4D sphere”. We achieved this by using a set of shrinking spatial spheres accordingly with decreased acquisition bandwidth (Fig.1). The 4D dataset was then reconstructed using the gridding method [9] after correlation step for SWIFT sequence.

Invivo studies were done on 3 nude mice. The superparamagnetic IONPs (EMG-308, Ferrotec, USA) coated with mesoporous silica and polyethylene glycol at concentrations of 0.16, 0.17, 0.18 mg Fe/(g of body weight) were delivered by intravenous (IV) injection. (1 mg Fe/ml = 17.8 mM Fe). Normal MB-SWIFT [8] images and 4D spectroscopic SWIFT images were acquired 1 week after IV injection on a 9.4 T animal MRI scanner (Agilent Technologies, USA) using a volume coil. MB-SWIFT: BW=384 kHz. Spectroscopic SWIFT: BWmax=125 kHz, bandwidth in frequency dimension Ω =15 kHz, total number of projections = 41792, acquisition time = 12 minutes. GRE images were also acquired with BW=150 kHz, TR=4.2 ms, TE=2.1 ms. The spectrum of each voxel was fitted to Lorentzian function to get T2*. [Fe] in organs were measured by ICP-MS.

Results and discussions

Images of post-injection mouse from the same slice, but at different frequencies are shown in Fig. 2, along with GRE and MB-SWIFT images. After injection, most IONPs deposited in liver, spleen, and kidney. These organs appeared as a void in GRE images due to the ultra-short T2* caused by IONPs at high concentration, while there are still plenty of signal in MB-SWIFT images. The presence of IONPs changes the water resonance frequencies of surrounding tissues. These were observed in spectroscopic SWIFT images at different frequencies (orange arrows fig.2) and in the spectrum over marked profile (red arrows fig.2). The B0 and susceptibility information can be further extracted. The image at fat frequency illustrated the peri-renal fat clearly (yellow arrows Fig. 2).

The spectroscopic images of a mouse body before and after IONPs-injection showed in left column of Fig.3. The spectroscopic information of liver, spleen and kidney, and the fitted T2* down to 20 microseconds were obtained (right part of Fig.3). Apparent line broadening effect was observed in the post-injection case for all three organs. In spleen, a binary distribution giving two very different T2* values was observed (Fig.3f), which was verified by histology showing majority of IONPs packed in red pulp rather than white pulp (Fig.4a and 4b). This can also be seen at MB-SWIFT images (Fig.4c). The acquired T2* map is shown in Fig.4d. Notice the fitted T2* values in spleen regions (white arrow heads) reflect the averaged values from both red and white pulps. A bi-component fitting could be used to fit components separately. Due to the limited resolution in the frequency dimension (Δf = 230 Hz), tissues with T2* higher than 1.5 ms cannot be accurately estimated. Compressed sensing will be used to increase frequency resolution while keep acquisition time in a reasonable range in future.

Conclusion

A 4D spectroscopic SWIFT technique was applied to characterize the bio-distribution of IONPs in vivo in mouse. Resonance frequency shift from susceptibility difference and T2* shortening effect (down to 20 microseconds) caused by IONPs was observed in liver, spleen and kidney. The acquired T2* map provides quantitative bio-distribution information of IONPs making the 4D spectroscopic SWIFT a promising tool in nanoparticle-based theranostics.
Conclusion A 4D spectroscopic SWIFT technique was applied to characterize the bio-distribution of IONPs in vivo in mouse. Resonance frequency shift from susceptibility difference and T2* shortening effect (down to 20 microseconds) caused by IONPs was observed in liver, spleen and kidney. The acquired T2* map provides quantitative bio-distribution information of IONPs making the 4D spectroscopic SWIFT a promising tool in nanoparticle-based theranostics.

Acknowledgements

This research was supported by BTRC P41 EB015894, WM KECK foundation and MN Futures Grant (UMN).

References

[1] D. Idiyatullin et al, ISMRM, 2009, No. 330

[2] F. Kiessling et al., Radiology, 2014, 273,1,10

[3] J. Zhang et al, ISMRM, 2015, No.225

[4] J. Zhang et al, Magn Reson Med, 2014,71,1982.

[5] J. Zhang et al, ISMRM, 2015, No.694

[6] C. Billotey et al, Magn Reson Med, 2003, 49, 646

[7] P. C. Lauterbur et al, J. Magn. Reson. 59, (1984) 536-541.

[8] D.Idiyatullin et al, J. Magn. Reson., 2015, 251, 19-25

[9] J. I. Jackson, et al., IEEE Trans. Med. Imaging (1991).

Figures

Fig.1 Sequence diagram for the 4D spectroscopic SWIFT. First row (RF) showed two representative TR cycles and the zoom-in elements . The figure describes 6 shrinking spatial hemispheres in time. The opposite hemispheres are acquired using inverted gradient directions.

Fig. 2 First row: 4D spectroscopic SWIFT images of IONPs-injected mouse body from the same slice but at different frequencies. Second row, from left to right: spectroscopy of spins at the orange dash line, MB-SWIFT and GRE images. Organs appeared as a void in GRE images due to the ultra-short T2*. The presence of IONPs changes the water resonance frequencies of surrounding tissues (orange and red arrows). The image at fat frequency illustrated the peri-renal fat clearly (yellow arrows).

Fig. 3 Left column: The images at water frequency of a mouse body before and after injection of IONPs. Right two columns: (a)-(f) The spectroscopy of representative ROI in three major organs, liver, spleen and kidney. The T2* values in (b), (d) and (f) are acquired by fitting the spectrum to Lorentzian function (solid line). The solid and dashed lines in (f) indicated bi-components distribution in spleen.

Fig. 4 Prussian blue staining histology of the spleen from control (a) and IONPs injected (b) mouse. Majority of IONPs in spleen were packed in red pulp rather than white pulp, which can also be identified from the axial view MB-SWIFT image (c) (red arrow). (d) T2* map of the mouse body in coronal view. Notice the much lower T2* values in areas of liver, kidneys and spleen (white dashed line).



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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