Quantitative susceptibility mapping of prostate cancer xenografts
Kofi Deh1, Marjan Zaman1, Padraic O'Malley1, Richard Lee1, Pascal Spincemaille1, and Yi Wang1

1Weill Cornell Medicine, New York, NY, United States

Synopsis

Quantitative susceptibility mapping (QSM) is a recently developed technique for quantifying magnetic susceptibility and it may be useful in quantifying super-paramagnetic iron oxide (SPIO) nanoparticles for prostate cancer therapy. Previously, researchers have been hampered in extending the use of this technique to cancers outside the brain because of problems such as chemical shift and a large dynamic susceptibility range. Recently developed algorithms, however, allow us to overcome these problems and we demonstrate their use for quantifying SPIO in a prostate cancer xenograft model for magnetic hyperthermia.

PURPOSE

Although, quantitative susceptibility mapping (QSM) is being extensively investigated as a biomarker in the brain [1], there are limited reports of its use elsewhere in the body. This is primarily because of the problems of chemical shift and high dynamic susceptibility range associated with extra-cranial applications. However, problems such as the quantification of superparamagnetic iron oxide nanoparticles (SPION) in-vivo for magnetic hyperthermia in prostate cancer, may benefit from QSM. Here we report the application of recently developed algorithms to perform QSM of prostate cancer xenografts in mice for in our project to determine the optimal time window for hyperthermia.

METHODS

8 Nu/Nu Balb C mice aged 8-10 weeks and bearing a LnCAP tumor in one flank were used for this study. One received 0.05 cc of 0.25 mg/cc Feraheme intratumorally and the rest received 2 mg Feraheme intravenously. The first mouse was sacrificed after injection and MR images were acquired using a birdcage mouse coil on a GE 3T scanner using a 3D multi-echo gradient echo sequence (FA = $$$15^0$$$, 11 echoes, ΔTE/TE1=4/3.9 ms, voxel size = 0.2, 0.2, 0.3 $$$mm^3$$$). Each of the other mice was imaged live with the same parameters at 1, 6, 12, 24, 48, 96 or 168 hours after injection, and then sacrificed for Prussian blue staining. To obtain a calibration constant for converting susceptibility measurements from QSM images to Feraheme mass, a falcon tube with serial dilutions of Feraheme in agar was imaged with the same acquisition parameters. QSM maps were reconstructed from the complex GRE data using the SPURS algorithm for spatial unwrapping and chemical shift correction [4], and the PDF and MEDIN algorithms for background field removal and dipole inversion respectively [5]. A weighting factor was used in MEDIN to accommodate the large susceptibility range. R2* maps were generated for comparison using the ARLO algorithm [6]. )). For the first mouse, the concentration of SPIO was estimated from the QSM image by taking the sum of the product of all voxel intensities and voxel size in the injection region, and multiplying by the mass susceptibility, K, obtained from the calibration procedure described above.

RESULTS

Figure 1 is the curve from the calibration experiment with the falcon tube and it determined the mass susceptibility of the Feraheme sample to be K = 213 ug/(mL * ppb). Figure 2 shows the R2*, QSM and a Prussian blue stain of a mouse tumor injected directly with Feraheme. By multiplying the calibration constant, K, with the total susceptibility in the region of interest shown in Figure 2, we obtained an estimate of about 0.011 ug, similar to the injected dose of 0.0125 ug. The QSM image obtained for a tumor in one of the live mice is shown in Figure 3. Prussian blue staining confirmed accumulation of SPIO at the boundary between the mouse body and the tumor. Figure 4 shows the QSM values obtained for the mice imaged at different time points. It shows the susceptibility values increasing till about 48 hours and then decreasing. This suggests that the optimal time window for performing magnetic hyperthermia is about 48 hours after SPIO injection. The negative susceptibility values for the last two time-points indicate complete removal of Feraheme from the tumor by the body resulting in tumor’s susceptibility value reverting to its baseline diamagnetic value.

DISCUSSION

Susceptibility maps of a mouse tumor, injected intratumorally with SPIO and imaged post-mortem, and of mice injected intravenously with SPIO and imaged live, were obtained using recently developed QSM algorithms. Prussian blue staining confirmed the presence of iron in the areas of high contrast on both R2* and QSM images. For the tumor imaged post-mortem, the amount of SPIO estimated from the QSM image was close to the amount injected. For live mice, the susceptibility estimate in the tumor increased till about 48 hours and then decreased, placing the optimal time window for hyperthermia at about 48 hours. We are currently pursuing the use of an independent method, Inductively Coupled Plasma Mass Spectrometry, to verify the amount of SPIO accumulated in the tumor of the mouse injected intravenously.

CONCLUSION

We demonstrate that QSM of SPIO prostate cancer xenografts can be performed using currently available algorithms. QSM appears promising for quantification of iron oxide particles in-vivo, although reproducibility studies need to be performed to confirm our results. The development of the use of QSM as a biomarker for magnetic hyperthermia treatment may help direct dosing and scheduling of treatment, as well as monitoring of treatment efficacy.

Acknowledgements

We acknowledge support from NIH grants RO1 EB013443, RO1 NS090464 and F31 EB019883.

References

[1], Wang and Liu, Quantitative susceptibility mapping (QSM): Decoding MRI data for a tissue magnetic biomarker, MRM, 82. 2015 [2] Pathak A., Magnetic resonance susceptibility based perfusion imaging of tumors using iron oxide nanoparticles, Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2009, 84-97 [3] Girard O. et al, Toward absolute quantification of iron oxide nanoparticles as well as cell internalized fraction using multiparametric MRI, Contrast Media Mol Imaging [4] Dong J. et al, Simultaneous phase unwrapping and removal of chemical shift (SPURS) using graph cuts: application in quantitative susceptibility mapping, IEEE Trans. Med. Imaging, 2015 [5] Tian L., et al, Nonlinear Formulation of the Magnetic Field to Source Relationship for Robust Quantitative Susceptibility Mapping, MRM 69:476 (2013) [6] Pei et al, Algorithm for fast monoexponential fitting based on Auto-Regression on Linear Operations (ARLO) of data, MRM, 73:845, 2015.

Figures

Calibration curve from experiment to determine mass susceptibility of a Feraheme sample.

MRI and histology results for a tumor directly injected with SPIO. Masking out air and bone tissue produced a better QSM map.

MRI and histology results for a tumor in a mouse injected intravenously with SPIO.

QSM measurements of mice imaged at different time-points.



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