title: Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer.
abstract: Pancreatic adenocarcinoma is a highly aggressive cancer, currently treated with limited success and dismal outcomes. New diagnostic and treatment strategies offer the potential to reduce cancer mortality. Developing highly specific noninvasive imaging probes for pancreatic cancer is essential to improving diagnostic accuracy and monitoring therapeutic intervention.
  
  
  
  A bispecific heterodimer was synthesized by conjugating an anti-tissue factor (TF) Fab with an anti-CD105 Fab, via the bio-orthogonal "click" reaction between tetrazine (Tz) and trans-cyclooctene (TCO). The heterodimer was labeled with (64)Cu for PET imaging of nude mice bearing BXPC-3 xenograft and orthotopic pancreatic tumors.
  
  
  
  PET imaging of BXPC-3 (TF/CD105(+/+)) xenograft tumors with (64)Cu-labeled heterodimer displayed significantly enhanced tumor uptake (28.8 ± 3.2 %ID/g; n = 4; SD) at 30 hours postinjection, as compared with each of their monospecific Fab tracers (12.5 ± 1.4 and 7.1 ± 2.6 %ID/g; n = 3; SD). In addition, the activity-concentration ratio allowed for effective tumor visualization (tumor/muscle ratio 75.2 ± 9.4 at 30 hours postinjection.; n = 4; SD). Furthermore, (64)Cu-NOTA-heterodimer enabled sensitive detection of orthotopic pancreatic tumor lesions with an uptake of 17.1 ± 4.9 %ID/g at 30 hours postinjection and tumor/muscle ratio of 72.3 ± 46.7.
  
  
  
  This study demonstrates that dual targeting of TF and CD105 provided synergistic improvements in binding affinity and tumor localization of the heterodimer. Dual-targeted imaging agents of pancreatic and other cancers may assist in diagnosing pancreatic malignancies as well as reliable monitoring of therapeutic response. Clin Cancer Res; 22(15); 3821-30. ©2016 AACR.
authors.affiliation: Department of Radiology, University of Wisconsin-Madison, Wisconsin.
authors.forename: Haiming
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Wisconsin.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: England
authors.affiliation: Materials Science Program, University of Wisconsin-Madison, Wisconsin.
authors.forename: Sixiang
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Wisconsin.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Graves
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Wisconsin.
authors.forename: Reinier
authors.initials: R
authors.lastname: Hernandez
authors.affiliation: Altor BioSciences, Miramar, Florida.
authors.forename: Bai
authors.initials: B
authors.lastname: Liu
authors.affiliation: TRACON Pharmaceuticals, Inc., San Diego, California.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Theuer
authors.affiliation: Altor BioSciences, Miramar, Florida.
authors.forename: Hing C
authors.initials: HC
authors.lastname: Wong
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Wisconsin.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nickles
authors.affiliation: Department of Radiology, University of Wisconsin-Madison, Wisconsin. Department of Medical Physics, University of Wisconsin-Madison, Wisconsin. Materials Science Program, University of Wisconsin-Madison, Wisconsin. University of Wisconsin Carbone Cancer Center, Madison, Wisconsin. wcai@uwhealth.org.
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D015415:Biomarkers; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D015260:Neprilysin / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods; D055503:Protein Multimerization; D019275:Radiopharmaceuticals; D013925:Thromboplastin / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D015415:Biomarkers; D007140:Immunoglobulin Fab Fragments; D019275:Radiopharmaceuticals; D013925:Thromboplastin; D015260:Neprilysin