uPAR-targeted multimodal tracer for pre- and intraoperative imaging in cancer surgery
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Martin C. Boonstra1,*, Pieter B.A.A. van Driel2,3,*, Danny M. van Willigen1,2, Marieke A. Stammes2,3, Hendrica A.J.M. Prevoo1, Quirijn R.J.G. Tummers1, Andrew P. Mazar4,5, Freek J. Beekman6,7, Peter J.K. Kuppen1, Cornelis J.H. van de Velde1, Clemens W.G.M. Löwik2, John V. Frangioni8, Fijs W.B. van Leeuwen2, Cornelis F.M. Sier1,9 and Alexander L. Vahrmeijer1
1 Department of Surgery, Leiden University Medical Center, Leiden, Netherlands
2 Department of Radiology, Leiden University Medical Center, Leiden, Netherlands
3 Percuros BV, Enschede, Netherlands
4 Department of Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA
5 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL, USA
6 MILabs, Utrecht, Netherlands
7 Section Radiation, Detection and Medical Imaging, Delft University of Technology, Delft, Netherlands
8 Curadel, LLC, Worcester, MA, USA
9 Antibodies for Research Applications BV, Gouda, Netherlands
* These authors have contributed equally to the study and share first authorship
Alexander L. Vahrmeijer, email:
Keywords: Image-guided surgery, near-infrared, SPECT, dual labeling, colorectal
Received: November 07, 2014 Accepted: March 03, 2015 Published: March 29, 2015
Pre- and intraoperative diagnostic techniques facilitating tumor staging are of paramount importance in colorectal cancer surgery. The urokinase receptor (uPAR) plays an important role in the development of cancer, tumor invasion, angiogenesis, and metastasis and over-expression is found in the majority of carcinomas. This study aims to develop the first clinically relevant anti-uPAR antibody-based imaging agent that combines nuclear (111In) and real-time near-infrared (NIR) fluorescent imaging (ZW800-1). Conjugation and binding capacities were investigated and validated in vitro using spectrophotometry and cell-based assays. In vivo, three human colorectal xenograft models were used including an orthotopic peritoneal carcinomatosis model to image small tumors. Nuclear and NIR fluorescent signals showed clear tumor delineation between 24h and 72h post-injection, with highest tumor-to-background ratios of 5.0 ± 1.3 at 72h using fluorescence and 4.2 ± 0.1 at 24h with radioactivity. 1-2 mm sized tumors could be clearly recognized by their fluorescent rim. This study showed the feasibility of an uPAR-recognizing multimodal agent to visualize tumors during image-guided resections using NIR fluorescence, whereas its nuclear component assisted in the pre-operative non-invasive recognition of tumors using SPECT imaging. This strategy can assist in surgical planning and subsequent precision surgery to reduce the number of incomplete resections.
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