Dual targeting of tissue factor and CD105 for preclinical PET imaging of pancreatic cancer

Haiming Luo, Christopher G. England, Sixiang Shi, Stephen A. Graves, Reinier Hernandez, Bai Liu, Charles P. Theuer, Hing C. Wong, Robert J. Nickles, Weibo Cai

Research output: Journal article publicationJournal articleAcademic researchpeer-review

20 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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 64Cu for PET imaging of nude mice bearing BXPC-3 xenograft and orthotopic pancreatic tumors. Results: PET imaging of BXPC-3 (TF/CD105+/+ ) xenograft tumors with64 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, 64Cu-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. Conclusions: This study demonstrates that dual targeting of TF and CD105 provided synergistic improvements in binding affinity and tumor localization of the heterodimer. Dualtargeted imaging agents of pancreatic and other cancers may assist in diagnosing pancreatic malignancies as well as reliable monitoring of therapeutic response.

Original languageEnglish
Pages (from-to)3821-3830
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number15
Early online date29 Mar 2016
DOIs
Publication statusPublished - 1 Aug 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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