Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics.
Laurel O SillerudAlexander J NeuweltFernanda I StaquiciniWadih ArapRenata PasqualiniPublished in: Cancers (2021)
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 T2-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 (~104/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.
Keyphrases
- contrast enhanced
- iron deficiency
- magnetic resonance imaging
- iron oxide
- high resolution
- adipose tissue
- diffusion weighted imaging
- magnetic resonance
- metal organic framework
- computed tomography
- mouse model
- aqueous solution
- deep learning
- visible light
- high fat diet
- endothelial cells
- high throughput
- type diabetes
- mesenchymal stem cells
- machine learning
- simultaneous determination
- insulin resistance
- stem cells
- label free
- single cell
- sensitive detection