Journal
CLINICAL CANCER RESEARCH
Volume 17, Issue 17, Pages 5695-5704Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-3420
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Funding
- American Cancer Society
- Department of Defense [W81XWH-06-1-0416, PR080717]
- NIH/NCI [R01CA130980, R01CA132566, P50 CA58207, R01CA140943, R21CA156124]
- Bay Area Breast Cancer Specialized Program of Research Excellence [P50 CA 58207]
- Stanford Center for Cancer Nanotechnology Excellence and Translation [U54 CA151459, P50 CA114747]
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Purpose: The presence of tumor-associated macrophages (TAM) in breast cancer correlates strongly with poor outcome. The purpose of this study was to develop a clinically applicable, noninvasive diagnostic assay for selective targeting and visualization of TAMs in breast cancer, based on magnetic resonanceI and clinically applicable iron oxide nanoparticles. Experimental Design: F4/80-negativemammary carcinoma cellsandF4/80-positiveTAMswere incubated with iron oxide nanoparticles and were compared with respect tomagnetic resonance signal changes and iron uptake. MMTV-PyMT transgenic mice harboring mammary carcinomas underwent nanoparticle-enhanced magnetic resonance imaging(MRI) upto 1 hour and 24 hours after injection. The tumor enhancement on MRIs was correlated with the presence and location of TAMs and nanoparticles by confocal microscopy. Results: In vitro studies revealed that iron oxide nanoparticles are preferentially phagocytosed by TAMs but not by malignant tumor cells. In vivo, all tumors showed an initial contrast agent perfusion on immediate postcontrast MRIs with gradual transendothelial leakage into the tumor interstitium. Twenty-four hours after injection, all tumors showed a persistent signal decline on MRIs. TAM depletion via alpha CSF1 monoclonal antibodies led to significant inhibition of tumor nanoparticle enhancement. Detection of iron using 3,3'-diaminobenzidine-enhanced Prussian Blue staining, combined with immunodetection of CD68, localized iron oxide nanoparticles to TAMs, showing that the signal effects on delayed MRIs were largely due to TAM-mediated uptake of contrast agent. Conclusion: These data indicate that tumor enhancement with clinically applicable iron oxide nanoparticles may serve as a new biomarker for long-term prognosis, related treatment decisions, and the evaluation of new immune-targeted therapies. Clin Cancer Res; 17(17); 5695-704. (C)2011 AACR.
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