A Novel Theranostic Combination of Near-infrared Fluorescence Imaging and Laser Irradiation Targeting c-KIT for Gastrointestinal Stromal Tumors

被引：27

作者：

Fujimoto, Shota ^{[1
]}

Muguruma, Naoki ^{[1
]}

Okamoto, Koichi ^{[1
]}

Kurihara, Takeshi ^{[1
]}

Sato, Yasushi ^{[1
]}

Miyamoto, Yoshihiko ^{[1
]}

Kitamura, Shinji ^{[1
]}

Miyamoto, Hiroshi ^{[1
]}

Taguchi, Takahiro ^{[2
]}

Tsuneyama, Koichi ^{[3
]}

Takayama, Tetsuji ^{[1
]}

机构：

[1] Tokushima Univ, Grad Sch Biomed Sci, Dept Gastroenterol & Oncol, 3-18-15 Kuramoto Cho, Tokushima 7708503, Japan

[2] Kochi Univ, Grad Sch Kuroshio Sci, Div Human Hlth & Med Sci, Nankoku, Kochi, Japan

[3] Tokushima Univ, Grad Sch Biomed Sci, Dept Pathol & Lab Med, Tokushima, Japan

来源：

THERANOSTICS | 2018年 / 8卷 / 09期

关键词：

gastrointestinal stromal tumors (GIST); c-KIT; fluorescence endoscopy; near-infrared photoimmunotherapy; PHOTODYNAMIC THERAPY; CELL-DEATH; SURFACE EXPRESSION; GASTRIC-CANCER; BREAST-CANCER; IN-VITRO; PHOTOIMMUNOTHERAPY; TOMOGRAPHY; RESISTANCE; ANTIBODIES;

D O I：

10.7150/thno.22027

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

It is difficult to distinguish gastrointestinal stromal tumors (GISTs) from other types of submucosal tumors under conventional gastrointestinal endoscopy. We aimed to detect GISTs by molecular fluorescence imaging using a near-infrared (NIR) photosensitizer (IR700)-conjugated anti-c-KIT antibody and to treat GISTs by photoimmunotherapy with NIR irradiation as a non-invasive theranostic procedure. We also investigated the therapeutic mechanisms. Methods: Human GIST cell lines GIST-T1 and GIST-882M were incubated with IR700-conjugated anti-c-KIT antibody, IR700-12A8, and observed by confocal laser microscopy. Mice with GIST-T1 xenografts or rats with orthotopic xenografts were injected with IR700-12A8 or AF488-conjugated antibody, and observed under IVIS or autofluorescence imaging (AFI) endoscopy. GIST cells were treated with IR700-12A8 and NIR light in vitro and vivo, and cell viability, histology and apoptosis were evaluated. Results: Strong red fluorescence of IR700-12A8 was observed on the cell membrane of GIST cells and was gradually internalized into the cytoplasm. Tumor-specific accumulation of IR700-12A8 was observed in GIST-T1 xenografts in mice. Under AFI endoscopy, a strong fluorescence signal was observed in orthotopic GIST xenografts in rats through the normal mucosa covering the tumor. The percentage of dead cells significantly increased in a light-dose-dependent manner and both acute necrotic and late apoptotic cell death was observed with annexin/PI staining. Cleaved PARP expression was significantly increased after IR700-12A8-mediated NIR irradiation, which was almost completely reversed by NaN3. All xenograft tumors (7/7) immediately regressed and 4/7 tumors completely disappeared after IR700-12A8-mediated NIR irradiation. Histologic assessment and TUNEL staining revealed apoptosis in the tumors. Conclusion: NIR fluorescence imaging using IR700-12A8 and subsequent NIR irradiation could be a very effective theranostic technology for GIST, the underlying mechanism of which appears to involve acute necrosis and supposedly late apoptosis induced by singlet oxygen.

引用

页码：2313 / 2328

页数：16

共 50 条

[1]

Akahoshi K, 2014, J GASTROINTEST LIVER, V23, P405, DOI 10.15403/jgld.2014.1121.234.eug

[2]

ASHMAN LK, 1991, BLOOD, V78, P30

[3]

Bashkatov A.N., 2007, Med. Laser Appl, V22, P95, DOI DOI 10.1016/J.MLA.2007.07.003

[4] Primitive acute myeloid leukemia cells with long-term proliferative ability in vitro and in vivo lack surface expression of c-kit (CD 117) [J].