title: Dual-energy micro-CT functional imaging of primary lung cancer in mice using gold and iodine nanoparticle contrast agents: a validation study.
abstract: OBJECTIVE
  To provide additional functional information for tumor characterization, we investigated the use of dual-energy computed tomography for imaging murine lung tumors. Tumor blood volume and vascular permeability were quantified using gold and iodine nanoparticles. This approach was compared with a single contrast agent/single-energy CT method. Ex vivo validation studies were performed to demonstrate the accuracy of in vivo contrast agent quantification by CT.
  
  
  METHODS
  Primary lung tumors were generated in LSL-Kras(G12D); p53(FL/FL) mice. Gold nanoparticles were injected, followed by iodine nanoparticles two days later. The gold accumulated in tumors, while the iodine provided intravascular contrast. Three dual-energy CT scans were performed-two for the single contrast agent method and one for the dual contrast agent method. Gold and iodine concentrations in each scan were calculated using a dual-energy decomposition. For each method, the tumor fractional blood volume was calculated based on iodine concentration, and tumor vascular permeability was estimated based on accumulated gold concentration. For validation, the CT-derived measurements were compared with histology and inductively-coupled plasma optical emission spectroscopy measurements of gold concentrations in tissues.
  
  
  RESULTS
  Dual-energy CT enabled in vivo separation of gold and iodine contrast agents and showed uptake of gold nanoparticles in the spleen, liver, and tumors. The tumor fractional blood volume measurements determined from the two imaging methods were in agreement, and a high correlation (R(2) = 0.81) was found between measured fractional blood volume and histology-derived microvascular density. Vascular permeability measurements obtained from the two imaging methods agreed well with ex vivo measurements.
  
  
  CONCLUSIONS
  Dual-energy CT using two types of nanoparticles is equivalent to the single nanoparticle method, but allows for measurement of fractional blood volume and permeability with a single scan. As confirmed by ex vivo methods, CT-derived nanoparticle concentrations are accurate. This method could play an important role in lung tumor characterization by CT.
authors: Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina, United States of America ; Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.
authors: Jeffrey R
authors: JR
authors: Ashton
authors: Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina, United States of America ; Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.
authors: Darin P
authors: DP
authors: Clark
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Everett J
authors: EJ
authors: Moding
authors: The Edward B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, Texas, United States of America.
authors: Ketan
authors: K
authors: Ghaghada
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America ; Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: David G
authors: DG
authors: Kirsch
authors: Department of Biomedical Engineering, Duke University, Durham, North Carolina, United States of America.
authors: Jennifer L
authors: JL
authors: West
authors: Center for In Vivo Microscopy, Duke University Medical Center, Durham, North Carolina, United States of America.
authors: Cristian T
authors: CT
authors: Badea
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001810:Blood Volume; D003287:Contrast Media; D006046:Gold; D007455:Iodine; D008081:Liposomes; D008168:Lung / Q000000981:diagnostic imaging / Q000473:pathology; D008175:Lung Neoplasms / Q000097:blood / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000473:pathology; D051379:Mice; D055806:Microvessels / Q000000981:diagnostic imaging / Q000473:pathology; D053758:Nanoparticles / Q000648:ultrastructure; D011877:Radionuclide Imaging; D015203:Reproducibility of Results; D047368:Tumor Burden; D055114:X-Ray Microtomography
chemical_list: D014408:Biomarkers, Tumor; D003287:Contrast Media; D008081:Liposomes; D006046:Gold; D007455:Iodine