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Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer.


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 (64)Cu for PET imaging of nude mice bearing BXPC-3 xenograft and orthotopic pancreatic tumors. RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Luo H 

PROVIDER: S-EPMC4970931 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Dual Targeting of Tissue Factor and CD105 for Preclinical PET Imaging of Pancreatic Cancer.

Luo Haiming H   England Christopher G CG   Shi Sixiang S   Graves Stephen A SA   Hernandez Reinier R   Liu Bai B   Theuer Charles P CP   Wong Hing C HC   Nickles Robert J RJ   Cai Weibo W  

Clinical cancer research : an official journal of the American Association for Cancer Research 20160329 15


<h4>Purpose</h4>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.<h4>Experimental design</h4>A bispecific heterodimer was synthesized by conjugating an anti-tissue factor (TF) Fab wi  ...[more]

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