Indocyanine green‐labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors

• Published in: Journal of gastroenterology and hepatology 2021-05, Vol.36 (5), p.1253-1262
• Main Authors: Fujimoto, Shota, Muguruma, Naoki, Nakao, Michiyasu, Ando, Hidenori, Kashihara, Takanori, Miyamoto, Yoshihiko, Okamoto, Koichi, Sano, Shigeki, Ishida, Tatsuhiro, Sato, Yasushi, Takayama, Tetsuji
• Format: Article
• Language: English
• Subjects: Animal models; Antitumor activity; Cell lines; c‐KIT; dasatinib; Endoscopy; fluorescence imaging; Fluorescent indicators; Gallbladder; gastrointestinal stromal tumor (GIST); Imatinib; indocyanine green (ICG); Intestine; Mucosa; near‐infrared (NIR); Protein-tyrosine kinase receptors; Xenografts
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.15281

Background and Aim It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c‐KIT, fluorescence‐labeled c‐KIT‐specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near‐infrared fluorescent imaging technology for GIST targeting c‐KIT using the novel fluorescent probe indocyanine green‐labeled dasatinib (ICG‐dasatinib) and to investigate the antitumor effect of ICG‐dasatinib on GIST cells. Methods Indocyanine green‐labeled dasatinib was synthesized by labeling linker‐induced dasatinib with ICG derivative 3‐indocyanine‐green‐acyl‐1,3‐thiazolidine‐2‐thione. Human GIST cell lines GIST‐T1 and GIST‐882M were incubated with ICG‐dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG‐dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG‐dasatinib and observed using an IVIS Spectrum. Results Strong fluorescent signals of ICG‐dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG‐dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2 nM in GIST‐T1 and 26.6, 3.63, and 47.6 nM in GIST‐882M cells, respectively. ICG‐dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. Conclusions Indocyanine green‐labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG‐dasatinib was preserved to the same degree as imatinib.