Tissue factor (TF) is the main initiator of the extrinsic coagulation cascade. However, TF also plays an important role in cancer. TF expression has been reported in 53-89% of all pancreatic adenocarcinomas and the expression level of TF has in clinical studies correlated with advanced stage, increased micro vessel density, metastasis and poor overall survival. Imaging of TF expression is of clinical relevance as a prognostic biomarker, and as a companion diagnostics for TF directed therapies currently under clinical development. Factor VII (FVII) is the natural ligand to TF. The purpose of this study was to investigate the possibility of using active site inhibited FVII (FVIIai) labeled with(64)Cu for PET imaging of TF expression.
FVIIai 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 ((64)Cu-NOTA-FVIIai). Longitudinal in vivo PET imaging was performed at 1, 4, 15 and 36 hours after injection of(64)Cu-NOTA-FVIIai in mice with pancreatic adenocarcinomas (BxPC-3). The specificity of TF imaging with(64)Cu-NOTA-FVIIai was investigated in subcutaneous pancreatic tumor models with different levels of TF expression and in a competition experiment. In addition, imaging of orthotopic pancreas tumors was performed using(64)Cu-NOTA-FVIIai and PET/MR imaging.In vivoimaging data were supported byex vivobiodistribution, flow cytometry and immunohistochemistry.
Longitudinal PET imaging with(64)Cu-NOTA-FVIIai showed a tumor uptake of 2.3 ± 0.2, 3.7 ± 0.3, 3.4 ± 0.3 and 2.4 ± 0.3 % injected dose per gram at 1, 4, 15 and 36 hours after injection, respectively. An increase in tumor to normal tissue contrast was observed over the imaging time-course. Competition with unlabeled FVIIai significantly (P< 0.001) reduced the tumor uptake. The tumor uptake observed in models with different TF expression levels was significantly different from each other (P< 0.001), and was in agreement with the TF level evaluated by TF immunohistochemistry staining. Orthotopic tumors were clearly visible on the PET/MR images and the uptake of(64)Cu-NOTA-FVIIai was co-localized with viable tumor tissue.
(64)Cu-NOTA-FVIIai is well suited for PET imaging of tumor TF expression, and imaging is capable of distinguishing the TF expression level of various pancreatic tumor models.
Copyright © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

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