title: Imaging Tumor Necrosis with Ferumoxytol.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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<0.001). Transendothelial USPIO leakage was significantly higher for 4T1 tumors (3.4±0.9x10-3 mL/min/100cm3) compared to MMTV-PyMT tumors (1.0±0.9x10-3 mL/min/100 cm3). Likewise, ferumoxytol imaging in patients showed similar findings with high T1 signal in areas of tumor necrosis and low signal in areas of intracellularly compartmentalized iron.
  
  
  CONCLUSIONS
  Differential T1- and T2-enhancement patterns of USPIO in tumors enable conclusions about their intracellular and extracellular location. This information can be used to characterize the composition of the tumor microenvironment.
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America.
authors.forename: Maryam
authors.initials: M
authors.lastname: Aghighi
authors.affiliation: School of Medicine, Tufts University, Medford, MA, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Golovko
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America.
authors.forename: Celina
authors.initials: C
authors.lastname: Ansari
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America.
authors.forename: Neyssa M
authors.initials: NM
authors.lastname: Marina
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Pisani
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America.
authors.forename: Lonnie
authors.initials: L
authors.lastname: Kurlander
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Klenk
authors.affiliation: GE Global Research Center, Research Circle, Niskayuna, NY, United States of America.
authors.forename: Srabani
authors.initials: S
authors.lastname: Bhaumik
authors.affiliation: University of California, Berkeley, CA, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Wendland
authors.affiliation: Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, United States of America.
authors.forename: Heike E
authors.initials: HE
authors.lastname: Daldrup-Link
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology*; D003287:Contrast Media / Q000737:chemistry; D003952:Diagnostic Imaging; D004195:Disease Models, Animal; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry*; D052203:Ferrosoferric Oxide / Q000737:chemistry*; D006801:Humans; D008279:Magnetic Resonance Imaging; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009336:Necrosis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D012516:Osteosarcoma / Q000473:pathology*; D010865:Pilot Projects; D012512:Sarcoma, Ewing / Q000473:pathology*
chemical_list: D003287:Contrast Media; D005290:Ferric Compounds; C000499:ferric oxide; D052203:Ferrosoferric Oxide