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Abstract
Purpose: Attenuated Salmonella typhimurium is a potential biotherapeutic antitumor agent because it can colonize tumors and inhibit their growth. The present study aimed to develop a doxycycline (Doxy)-inducible gene switch system in attenuated S. typhimurium and assess its therapeutic efficacy in various tumor-bearing mice models.

Procedures: A Doxy-inducible gene switch system comprising two plasmids was engineered to trigger the expression of cargo genes (Rluc8 and clyA). Attenuated S. typhimurium carrying Rluc8 were injected intravenously into BALB/c mice bearing CT26 tumors, and bioluminescence images were captured at specified intervals post-administration of doxycycline. The tumor-suppressive effects of bacteria carrying clyA were evaluated in BALB/c mice bearing CT26 tumors and in C57BL/6 mice bearing MC38 tumors.

Results: Expression of the fimE gene, induced only in the presence of Doxy, triggered a unidirectional switch of the POXB20 promoter to induce expression of the cargo genes. The switch event was maintained over a long period of bacterial culture. After intravenous injection of transformed Salmonella into mice bearing CT26 tumors, the bacteria transformed with the Doxy-inducible gene switch system for Rluc8 targeted only tumor tissues and expressed the payloads 2 days after Doxy treatment. Notably, bacteria carrying the Doxy-inducible gene switch system for clyA effectively suppressed tumor growth and prolonged survival, even after just one Doxy induction.

Conclusions: These results suggest that attenuated S. typhimurium carrying this novel gene switch system elicited significant therapeutic effects through a single induction triggering and were a potential biotherapeutic agent for tumor therapy.

Affiliations

Hien Thi-Thu Ngo 1 2 3, Dinh-Huy Nguyen 1 2, Sung-Hwan You 1 4, Khuynh Van Nguyen 1 2, So-Young Kim 1 4, Yeongjin Hong 5 6, Jung-Joon Min 7 8 9 10
1Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea.
2Department of Molecular Medicine (BrainKorea21 Plus), Chonnam National University Graduate School, Gwangju, 61469, Republic of Korea.
3Department of Biochemistry, Hanoi Medical University, No 1, Ton That Tung St., Dong Da, Hanoi, 100000, Vietnam.
4CNCure Biotech, Hwasun, 58128, Republic of Korea.
5CNCure Biotech, Hwasun, 58128, Republic of Korea. yjhong@jnu.ac.kr.
6Department of Microbiology, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea. yjhong@jnu.ac.kr.
7Institute for Molecular Imaging and Theranostics, Chonnam National University Medical School, Gwangju, 61469, Republic of Korea. jjmin@jnu.ac.kr.
8Department of Molecular Medicine (BrainKorea21 Plus), Chonnam National University Graduate School, Gwangju, 61469, Republic of Korea. jjmin@jnu.ac.kr.
9CNCure Biotech, Hwasun, 58128, Republic of Korea. jjmin@jnu.ac.kr.
10Department of Nuclear Medicine, Chonnam National University Medical School and Hwasun Hospital, Gwangju, 61469, Republic of Korea. jjmin@jnu.ac.kr.