title: Immuno-PET of tissue factor in pancreatic cancer.
abstract: Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types. The goal of this study was to develop a PET tracer for imaging of TF expression in pancreatic cancer.
  
  
  METHODS
  ALT-836, a chimeric antihuman TF monoclonal antibody, was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with (64)Cu. To compare the TF binding affinity of ALT-836 and NOTA-ALT-836, flow cytometry analysis was performed in 3 pancreatic cancer cell lines with different expression levels of TF (from low to high: PANC-1, ASPC-1, and BXPC-3). PET, biodistribution, blocking, and histology studies were performed on pancreatic tumor-bearing mice to evaluate the ability and specificity of (64)Cu-NOTA-ALT-836 to target TF in vivo.
  
  
  RESULTS
  There was no difference in TF binding affinity between ALT-836 and NOTA-ALT-836. (64)Cu-labeling was achieved with high yield and specific activity. Serial PET revealed that the uptake of (64)Cu-NOTA-ALT-836 in BXPC-3 tumors (high TF expression) was 5.7 ± 1.8, 10.4 ± 0.8, and 16.5 ± 2.6 percentage injected dose per gram at 4, 24, and 48 h after injection, respectively (n = 4), significantly higher than that in the PANC-1 and ASPC-1 tumors. Biodistribution data as measured by γ-counting were consistent with the PET findings. Blocking experiments and histology further confirmed the TF specificity of (64)Cu-NOTA-ALT-836.
  
  
  CONCLUSIONS
  Herein we report the first successful PET imaging of TF expression. Persistent and TF-specific uptake of (64)Cu-NOTA-ALT-836 was observed in pancreatic cancer models.
authors.affiliation: Department of Radiology, University of Wisconsin, Madison, WI, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Tapas R
authors.initials: TR
authors.lastname: Nayak
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Engle
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
authors.forename: Bai
authors.initials: B
authors.lastname: Liu
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology; D051379:Mice; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics; D013925:Thromboplastin / Q000276:immunology / Q000378:metabolism*
chemical_list: C572574:ALT-836; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D007074:Immunoglobulin G; D011994:Recombinant Proteins; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid; D013925:Thromboplastin