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2015 ; 10
(11
): e0142665
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Imaging Tumor Necrosis with Ferumoxytol
#MMPMID26569397
Aghighi M
; Golovko D
; Ansari C
; Marina NM
; Pisani L
; Kurlander L
; Klenk C
; Bhaumik S
; Wendland M
; Daldrup-Link HE
PLoS One
2015[]; 10
(11
): e0142665
PMID26569397
show ga
OBJECTIVE: Ultra-small superparamagnetic iron oxide nanoparticles (USPIO) are
promising contrast agents for magnetic resonance imaging (MRI). USPIO mediated
proton relaxation rate enhancement is strongly dependent on compartmentalization
of the agent and can vary depending on their intracellular or extracellular
location in the tumor microenvironment. We compared the T1- and T2-enhancement
pattern of intracellular and extracellular USPIO in mouse models of cancer and
pilot data from patients. A better understanding of these MR signal effects will
enable non-invasive characterizations of the composition of the tumor
microenvironment. MATERIALS AND METHODS: Six 4T1 and six MMTV-PyMT mammary tumors
were grown in mice and imaged with ferumoxytol-enhanced MRI. R1 relaxation rates
were calculated for different tumor types and different tumor areas and compared
with histology. The transendothelial leakage rate of ferumoxytol was obtained by
our measured relaxivity of ferumoxytol and compared between different tumor
types, using a t-test. Additionally, 3 patients with malignant sarcomas were
imaged with ferumoxytol-enhanced MRI. T1- and T2-enhancement patterns were
compared with histopathology in a descriptive manner as a proof of concept for
clinical translation of our observations. RESULTS: 4T1 tumors showed central
areas of high signal on T1 and low signal on T2 weighted MR images, which
corresponded to extracellular nanoparticles in a necrotic core on histopathology.
MMTV-PyMT tumors showed little change on T1 but decreased signal on T2 weighted
images, which correlated to compartmentalized nanoparticles in tumor associated
macrophages. Only 4T1 tumors demonstrated significantly increased R1 relaxation
rates of the tumor core compared to the tumor periphery (p<0.001).
Transendothelial USPIO leakage was significantly higher for 4T1 tumors
(3.4±0.9x10-3 mL/min/100cm3) compared to MMTV-PyMT tumors (1.0±0.9x10-3
mL/min/100 cm3). Likewise, ferumoxytol imaging in patients showed similar
findings with high T1 signal in areas of tumor necrosis and low signal in areas
of intracellularly compartmentalized iron. CONCLUSION: Differential T1- and
T2-enhancement patterns of USPIO in tumors enable conclusions about their
intracellular and extracellular location. This information can be used to
characterize the composition of the tumor microenvironment.
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