Visualizing cancer and response to therapy in vivo using Cy5.5-labeled factor VIIa and anti-tissue factor antibody

• Type of Material: Article
• Authors: Shijun Zhu, Emory University; Walter Kisiel, University of New Mexico; Yang J. Lu, Emory University; Lars C. Petersen, Novo Nordisk AS; John M. Ndungu, Emory University; Terry W. Moore, Emory University; Ernest T. Parker, Emory University; Aiming Sun, Emory University; Jann N. Sarkaria, Mayo Clinic; James Snyder, Emory University; Dennis C Liotta, Emory University; Daniel J Brat, Emory University; Bassel El-Rayes, Emory University; Mamoru Shoji, Emory University
• Language: English
• Date: 2015-04-01
• Publisher: Informa Healthcare
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.
• Final Published Version (URL): http://dx.doi.org/10.3109/1061186X.2014.988217
• Title of Journal or Parent Work: Journal of Drug Targeting
• ISSN: 1061-186X
• Volume: 23
• Issue: 3
• Start Page: 257
• End Page: 265
• Grant/Funding Information: This research was supported by Georgia Cancer Coalition (#00026700) (BFE); the U.S. Department of Defense, Division of U.S. Army DAMD17-00-1-0241 and W81XWH-08-1-0494 (MS, SZ, YJL, TWM, JMN, AS, JPS); the National Institutes of Health (NIH) grant R21CA82995-01A1, 1 R21 CA139035-01A1 (MS, DJB, SZ, TWM, JMN, AS, JPS); and the Emory Institute for Drug Development (TWM, JMN, AS, JPS, DCL); CA108961, CA25224, and CA114740 (JNS); American Cancer Society Research Scholar Grant (JNS); and Accelerate Brain Cancer Cure (JNS).
• Keywords: DELIVERY; COAGULATION; tumor targeting; ANGIOGENESIS; TISSUE FACTOR EXPRESSION; THROMBOSIS; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Drug delivery; factor VIIa inhibitor; PANCREATIC-CANCER; PROCOAGULANT ACTIVITY; ACTIVATION; tissue factor; TUMOR-CELLS; ENDOTHELIAL GROWTH-FACTOR; Science & Technology
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

We have developed a specific technique for imaging cancer in vivo using Cy5.5-labeled factor VIIa (fVIIa), clotting-deficient FFRck-fVIIa, paclitaxel-FFRck-fVIIa, and anti-tissue factor (TF) antibody. FVIIa is the natural ligand for TF. We took advantage of the fact that vascular endothelial cells (VECs) in cancer, but not normal tissue, aberrantly express TF due to its induction by vascular endothelial growth factor (VEGF). Under physiological conditions, TF is expressed by stromal cells and outer blood vessel layers (smooth muscle and adventitia), but not by VECs. We hypothesized that labeled fVIIa or anti-TF antibodies could be used to image the tumor vasculature in vivo. To test this, Cy5.5-labeled fVIIa, FFRck-fVIIa, paclitaxel-FFRck-fVIIa, and anti-TF antibody were developed and administered to athymic nude mice carrying xenografts including glioma U87EGFRviii, pancreatic cancer ASPC-1 and Mia PaCa-2, and squamous cell carcinoma KB-V1. Cy5.5 labeled with these targeting proteins specifically localized to the tumor xenografts for at least 14 days but unconjugated Cy5.5 did not localize to any xenografts or organs. This method of imaging TF in the tumor VECs may be useful in detecting primary tumors and metastases as well as monitoring in vivo therapeutic responses.