ID | 111436 |
Title Alternative | c-KITを標的としたGastrointestinal stromal tumorsに対する近赤外蛍光イメージングとレーザー照射の新しいセラノスティクス
|
Author |
Fujimoto, Shota
Tokushima University
Muguruma, Naoki
Tokushima University
Tokushima University Educator and Researcher Directory
KAKEN Search Researchers
Okamoto, Koichi
Tokushima University
Tokushima University Educator and Researcher Directory
KAKEN Search Researchers
Kurihara, Takeshi
Tokushima University
Miyamoto, Yoshihiko
Tokushima University
Miyamoto, Hiroshi
Tokushima University
Tokushima University Educator and Researcher Directory
KAKEN Search Researchers
Taguchi, Takahiro
Tokushima University
|
Keywords | gastrointestinal stromal tumors (GIST)
c-KIT
fluorescence endoscopy
near-infrared photoimmunotherapy
|
Content Type |
Thesis or Dissertation
|
Description | 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. |
Journal Title |
Theranostics
|
ISSN | 18387640
|
Publisher | Ivyspring International Publisher
|
Volume | 8
|
Issue | 9
|
Start Page | 2313
|
End Page | 2328
|
Published Date | 2018-03-21
|
Remark | 内容要旨・審査要旨・論文本文の公開
本論文は,著者Shota Fujimotoの学位論文として提出され,学位審査・授与の対象となっている。 |
Rights | © 2018 Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
|
EDB ID | |
DOI (Published Version) | |
URL ( Publisher's Version ) | |
FullText File | |
language |
eng
|
TextVersion |
ETD
|
MEXT report number | 甲第3130号
|
Diploma Number | 甲医第1364号
|
Granted Date | 2018-03-23
|
Degree Name |
Doctor of Medical Science
|
Grantor |
Tokushima University
|
departments |
Medical Sciences
University Hospital
|