Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics
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 intraveno...
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doaj-29c1816bb0db4764a5bf2dd9a6c1e24c2021-08-06T15:20:33ZengMDPI AGCancers2072-66942021-07-01133802380210.3390/cancers13153802Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION DynamicsLaurel O. Sillerud0Alexander J. Neuwelt1Fernanda I. Staquicini2Wadih Arap3Renata Pasqualini4Department of Neurology, UNM BRaIN Center, University of New Mexico School of Medicine, Albuquerque, NM 87106, USADivision of Hematology, Oncology and Palliative Care, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USARutgers Cancer Institute of New Jersey, Newark, NJ 07103, USARutgers Cancer Institute of New Jersey, Newark, NJ 07103, USARutgers Cancer Institute of New Jersey, Newark, NJ 07103, USATumor-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<sub>2</sub>-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<sup>4</sup>/cell) by the F4/80<sup>+</sup>CD11b<sup>+</sup> 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<sup>+</sup>CD11b<sup>+</sup> TAMs infiltrated the tumors and accumulated SPION iron. Our methodology and findings have translational applications for breast cancer patients.https://www.mdpi.com/2072-6694/13/15/3802ferumoxytoltriple-negative breast cancerMRI[Fe]MRI |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Laurel O. Sillerud Alexander J. Neuwelt Fernanda I. Staquicini Wadih Arap Renata Pasqualini |
spellingShingle |
Laurel O. Sillerud Alexander J. Neuwelt Fernanda I. Staquicini Wadih Arap Renata Pasqualini Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics Cancers ferumoxytol triple-negative breast cancer MRI [Fe]MRI |
author_facet |
Laurel O. Sillerud Alexander J. Neuwelt Fernanda I. Staquicini Wadih Arap Renata Pasqualini |
author_sort |
Laurel O. Sillerud |
title |
Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics |
title_short |
Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics |
title_full |
Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics |
title_fullStr |
Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics |
title_full_unstemmed |
Repurposing Ferumoxytol as a Breast Cancer-Associated Macrophage Tracer with Five-Dimensional Quantitative [Fe]MRI of SPION Dynamics |
title_sort |
repurposing ferumoxytol as a breast cancer-associated macrophage tracer with five-dimensional quantitative [fe]mri of spion dynamics |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-07-01 |
description |
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<sub>2</sub>-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<sup>4</sup>/cell) by the F4/80<sup>+</sup>CD11b<sup>+</sup> 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<sup>+</sup>CD11b<sup>+</sup> TAMs infiltrated the tumors and accumulated SPION iron. Our methodology and findings have translational applications for breast cancer patients. |
topic |
ferumoxytol triple-negative breast cancer MRI [Fe]MRI |
url |
https://www.mdpi.com/2072-6694/13/15/3802 |
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