RESEARCH ARTICLE

Imaging Tumor Necrosis with Ferumoxytol Maryam Aghighi1, Daniel Golovko2, Celina Ansari1, Neyssa M. Marina1, Laura Pisani1, Lonnie Kurlander1, Christopher Klenk1, Srabani Bhaumik3, Michael Wendland4, Heike E. Daldrup-Link1* 1 Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America, 2 School of Medicine, Tufts University, Medford, MA, United States of America, 3 GE Global Research Center, Research Circle, Niskayuna, NY, United States of America, 4 University of California, Berkeley, CA, United States of America * [email protected]

Abstract Objective

OPEN ACCESS Citation: Aghighi M, Golovko D, Ansari C, Marina NM, Pisani L, Kurlander L, et al. (2015) Imaging Tumor Necrosis with Ferumoxytol. PLoS ONE 10(11): e0142665. doi:10.1371/journal.pone.0142665 Editor: Efstathios Karathanasis, Case Western Reserve University, UNITED STATES

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.

Received: July 11, 2015

Materials and Methods

Accepted: October 26, 2015

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.

Published: November 16, 2015 Copyright: © 2015 Aghighi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper. Funding: The authors acknowledge support from the National Cancer Institute, grant number R21CA176519 and the Eunice Kennedy Shriver National Institute for Child Health and Human Development, grant number R01-HD081123. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.

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

Imaging Tumor Necrosis with Ferumoxytol.

Ultra-small superparamagnetic iron oxide nanoparticles (USPIO) are promising contrast agents for magnetic resonance imaging (MRI). USPIO mediated prot...
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