Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics

SIMPLE SUMMARY: With the incorporation of immune-modulating therapies into the standard management of triple-negative breast cancer, there is increased interest in the non-invasive imaging of the tumor immune microenvironment. Ferumoxytol is FDA-approved as an iron replacement therapy for iron-deficiency anemia and is also a superparamagnetic iron oxide nanoparticle (SPION) resulting in negative enhancement on T(2)-weighted MR imaging. It has previously been established that ferumoxytol is taken up by macrophages. In the current study, we used ferumoxytol-contrasted MRI to quantitatively image the iron concentration, and, by extension, the tumor-associated macrophage infiltration within the tumor microenvironment of a highly inflammatory model of triple-negative breast cancer. ABSTRACT: Tumor-associated macrophages (TAMs) in breast cancer regulate inflammation, immunosuppression, angiogenesis, and metastasis. However, TAM imaging remains a clinical challenge. Ferumoxytol has long been an FDA-approved superparamagnetic iron oxide nanoparticle (SPION) preparation used as an intravenous (IV) treatment for iron-deficiency anemia. Given its high transverse relaxivity, ferumoxytol produces a negative image contrast upon cellular uptake in T(2)-weighted magnetic resonance imaging (MRI) studies. Here we evaluated ferumoxytol as a contrast agent to image/quantify TAMs in an aggressive mouse model of breast cancer: We developed [Fe]MRI to measure the 5-dimensional function c(x,y,z,t), where c is the concentration of nanoparticle iron and {x,y,z,t} is the 4-dimensional set of tumor space-time coordinates. Ferumoxytol SPIONs are readily phagocytosed (~10(4)/cell) by the F4/80(+)CD11b(+) TAMs within breast tumors. Quantitative [Fe]MRIs served to determine both the spatial and the temporal distribution of the SPION iron, and hence to measure [Fe] = c(x,y,z,t), a surrogate for TAM density. In single-dose pharmacokinetic studies, after an IV dose of 5 mg/Kg iron, [Fe]MRI measurements showed that c(x,y,z,t) within breast tumors peaked around [Fe] = 70 μM at 42 h post-administration, and decayed below the [Fe]MRI detection limit (~2 μM) by day 7. There was no SPION uptake in control organs (muscle and adipose tissue). Optical microscopy of tissue sections confirmed that F4/80(+)CD11b(+) TAMs infiltrated the tumors and accumulated SPION iron. Our methodology and findings have translational applications for breast cancer patients.