2018 Fiscal Year Research-status Report
In vivo Click Reaction of Acrolein: Application to In vivo Synthetic Chemistry and Cancer Imaging
| Project/Area Number |
18K14341
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
PRADIPTA AMBARA 国立研究開発法人理化学研究所, 開拓研究本部, 基礎科学特別研究員 (90631648)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | Acrolein / Phenyl azide / Click reaction / Breast cancer / TAMRA / Intraoperative detection / Imaging / Cancer surgery |
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| Outline of Annual Research Achievements |
In fiscal year 2018, we utilize click reaction of endogenous acrolein to discriminate breast cancer lesion from normal breast gland which resected from breast cancer patients. Previously, we uncovered the 1,3-dipolar cycloaddition reaction between phenyl azide and acrolein, which proceeded under physiological conditions, even without a catalyst, to give the 4-formyl-1,2,3-triazoline derivative. Herein, by attaching TAMRA fluorophore to the phenyl azide, we could use the click reaction to selectively and sensitively detect arolein in various human cell lines.
We demonstrated the feasibility of using TAMRA-labeled phenyl azide-acrolein reaction to determine the acrolein levels in various human cell lines and found that cancer cells have higher levels of acrolein compared to normal cells. Based on the observation that acrolein is produced by cancer cells in significant amounts, we hypothesized that TAMRA-labeled phenyl azide could selectively and sensitively detect acrolein in cancerous tissues. Thus, we utilized TAMRA-labeled phenyl azide to detect acrolein in breast cancer tissues resected from breast cancer patients. The results were beyond our expectation. Our findings indicated that acrolein detection in cancerous tissues using TAMRA-labeled phenyl azide lead to the clear observation of the fluorescence image that can be used to discriminate morphology of the labeled tissues. Because only the cancer cells were labeled selectively by TAMRA-labeled phenyl azide, this method might be useful for rapid intraoperative diagnosis during breast conserving surgery.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
We have successfully utilized the click reaction as a simple and robust method for detecting acrolein generated by live cells. Moreover, we were able to show that TAMRA-labeled phenyl azide clearly and rapidly discriminated breast cancers from normal breast gland in live tissues from patients, not only imaging the presence of cancer lesions but also showing their morphological features only within few minutes. This new method has the potential to become a new margin management method of live tissues with high selectivity, and could be used as discriminative, low-cost, and easy-to-perform method for cancer sensing during surgery.
This organic synthetic chemistry-based method is going to be confirmed in a clinical prospective study including intraoperative assessment of resection stumps in breast cancer patients. The results of these findings appeared in the Advanced Science journal, and the press releases received wide coverage.
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| Strategy for Future Research Activity |
This research is divided in two parts; the first part of this work consisted of the cancer treatment; and the second part consisted of the cancer imaging. Both parts utilize the in vivo click reaction of endogenous acrolein as the key reaction. In fiscal year 2018, we achieved excellent outcome for the second part. We observed that TAMRA-labeled phenyl azide could react with endogenous acrolein to selectively labeled the breast cancer lesions and visualize their tissue morphologies.
Based on these results, in fiscal year 2019, the research will focus on the first part, i.e. cancer treatment. Several caged drugs (anticancer compounds) will be attached to the phenyl azide, and the corresponding azide-acrolein click reaction will be used to treat the cancer. This caged drug-conjugated phenyl azide is non-toxic against the cells. However, the drug-conjugated phenyl azide could react with endogenous acrolein, which significantly overexpressed in cancer cells, to release and activate the anticancer drug in cancer cells. In other words, the azide-acrolein “click-to-release" reaction will selectively occur only at the cancer cells to activate the anticancer drug only at the target area and leave the normal cells intact.
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Research Products
(16 results)
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[Journal Article] Cascade Reaction in Human Live Tissue Allows Clinically Applicable Diagnosis of Breast Cancer Morphology2019
Author(s)
Tomonori Tanei, Ambara R. Pradipta, Koji Morimoto, Motoko Fujii, Mayumi Arata, Akihiro Ito, Minoru Yoshida, Elena Saigitbatalova, Almira Kurbangalieva, Jun-ichiro Ikeda, Eiichi Morii, Shinzaburo Noguchi, Katsunori Tanaka
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Journal Title
Advanced Science
Volume: 6
Pages: 1801479
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Poster Abstracts I2019
Author(s)
Tomonori Tanei, Ambara R. Pradipta, Koji Morimoto, Motoko Fujii, Jun-ichiro Ikeda, Eiichi Morii, Shinzaburo Noguchi, Koichi Tanaka,
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Journal Title
The Breast
Volume: 44
Pages: S26～S27
DOI
Peer Reviewed / Int'l Joint Research
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[Journal Article] In vitro and in vivo cancer cell apoptosis triggered by competitive binding of Cinchona alkaloids to the RING domain of TRAF62018
Author(s)
Yonghao Qi, Xuan Zhao, Jiaying Chen, Ambara R. Pradipta, Jing Wei, Haihua Ruan, Lijun Zhou, Richard P Hsung, Katsunori Tanaka
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Journal Title
Bioscience, Biotechnology, and Biochemistry
Volume: 12
Pages: 1～16
DOI
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Poster Abstract2018
Author(s)
Ambara R. Pradipta, Elena Saigitbatalova, Almira Kurbangalieva, Katsunori Tanaka
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Journal Title
European Journal of Clinical Investigation
Volume: 48
Pages: 219
DOI
Peer Reviewed / Int'l Joint Research
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