TY - JOUR
T1 - uPAR-targeted multimodal tracer for pre- and intraoperative imaging in cancer surgery
AU - Boonstra, Martin C.
AU - van Driel, Pieter B A A
AU - van Willigen, Danny M.
AU - Stammes, Marieke A.
AU - Prevoo, Hendrica A J M
AU - Tummers, Quirijn R J G
AU - Mazar, Andrew P.
AU - Beekman, Freek J.
AU - Kuppen, Peter J K
AU - van de Velde, Cornelis J H
AU - Löwik, Clemens W G M
AU - Frangioni, John V.
AU - van Leeuwen, Fijs W B
AU - Sier, Cornelis F M
AU - Vahrmeijer, Alexander L.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Colorectal
KW - Dual labeling
KW - Image-guided surgery
KW - Near-infrared
KW - SPECT
UR - http://www.scopus.com/inward/record.url?scp=84931065242&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84931065242&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3680
DO - 10.18632/oncotarget.3680
M3 - Article
C2 - 25895028
AN - SCOPUS:84931065242
SN - 1949-2553
VL - 6
SP - 14260
EP - 14273
JO - Oncotarget
JF - Oncotarget
IS - 16
ER -
