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
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