title: MRI-monitored transcatheter intra-arterial delivery of SPIO-labeled natural killer cells to hepatocellular carcinoma: preclinical studies in a rodent model.
abstract: OBJECTIVE
  The objective of this study was to test the hypotheses that intra-arterial infusion allows for targeted natural killer (NK) lymphocyte delivery to hepatocellular carcinoma (HCC) and that iron oxide labeling allows for quantitative visualization of intra-arterial NK delivery with magnetic resonance imaging (MRI).
  
  
  METHODS
  Experiments received approval from the institutional animal care and use committee. NK-92MI cells were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Cell viability, labeling efficacy, and cell phantom imaging studies were performed. Eighteen rats were each implanted with HCC tumors. Catheter was placed in proper hepatic artery for either NK lymphocyte (12 rats) or saline (6 rats) infusion. For the 6 rats, MRI T2* measurements for tumor and normal liver were compared before and after the NK infusion and correlated with histologic measurements. Prussian blue staining was used for labeled NK identification. The remaining rats survived for 8 days after the infusion to compare tumor size changes in the rats that received NK cell (6 rats) or saline (6 rats) infusions. Spearman correlation coefficients and t tests were calculated for statistical analyses.
  
  
  RESULTS
  Increasing SPIO incubation concentration decreased cell viability. Labeling efficacy mean (SD) was 88.0% (3.1%) across samples. The spatial extent of T2*-weighted contrast and R2* relaxivity values increased for cell phantom samples incubated with increasing SPIO concentrations. T2* measurements decreased in the tumor and normal liver tissues after the NK infusion (P < 0.001); ΔT2* was greater in the tumors than in the normal liver tissue (P < 0.001). Histologic measurements demonstrated increased NK delivery to the tumor compared with the normal liver (P < 0.001). ΔT2* was well correlated with histologic NK measurements (ρ = 0.70). Changes in tumor diameter 8 days after the infusion were significantly different between those rats that received NK cell infusions (-2.49 [0.86] mm) and those that received sham saline infusion (5.23 [0.66] mm).
  
  
  CONCLUSIONS
  Intra-arterial infusion permitted selective delivery of NK cells to HCC. Transcatheter delivery of SPIO-labeled NK cells can be quantitatively visualized with MRI. Transcatheter NK cell delivery limited tumor size progression compared with controls.
authors.affiliation: Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Sheu
authors.forename: Zhuoli
authors.initials: Z
authors.lastname: Zhang
authors.forename: Reed A
authors.initials: RA
authors.lastname: Omary
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Larson
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000601:surgery*; D002406:Catheterization, Peripheral / Q000379:methods*; D045744:Cell Line, Tumor; D058948:Cell Tracking / Q000379:methods; D003287:Contrast Media; D003911:Dextrans; D007694:Killer Cells, Natural / Q000637:transplantation*; D008113:Liver Neoplasms / Q000473:pathology / Q000601:surgery*; D053783:Magnetic Resonance Imaging, Interventional / Q000379:methods*; D058185:Magnetite Nanoparticles; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013194:Staining and Labeling / Q000379:methods; D016896:Treatment Outcome
chemical_list: D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; C097921:ferumoxtran-10