Prodrug-conjugated tumor-seeking commensals for targeted cancer therapy

Haosheng Shen, Changyu Zhang, Shengjie Li, Yuanmei Liang, Li Ting Lee, Nikhil Aggarwal, Kwok Soon Wun, Jing Liu, Saravanan Prabhu Nadarajan, Cheng Weng, Hua Ling, Joshua K. Tay, Wang De Yun, Shao Q. Yao, In Young Hwang (), Yung Seng Lee and Matthew Wook Chang ()
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Haosheng Shen: National University of Singapore
Changyu Zhang: Ningbo Institute of Dalian University of Technology
Shengjie Li: National University of Singapore
Yuanmei Liang: National University of Singapore
Li Ting Lee: National University of Singapore
Nikhil Aggarwal: National University of Singapore
Kwok Soon Wun: National University of Singapore
Jing Liu: Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore
Saravanan Prabhu Nadarajan: National University of Singapore
Cheng Weng: National University of Singapore
Hua Ling: National University of Singapore
Joshua K. Tay: National University of Singapore
Wang De Yun: Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore
Shao Q. Yao: National University of Singapore
In Young Hwang: National University of Singapore
Yung Seng Lee: National University of Singapore
Matthew Wook Chang: National University of Singapore

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Prodrugs have been explored as an alternative to conventional chemotherapy; however, their target specificity remains limited. The tumor microenvironment harbors a range of microorganisms that potentially serve as tumor-targeting vectors for delivering prodrugs. In this study, we harness bacteria-cancer interactions native to the tumor microbiome to achieve high target specificity for prodrug delivery. We identify an oral commensal strain of Lactobacillus plantarum with an intrinsic cancer-binding mechanism and engineer the strain to enable the surface loading of anticancer prodrugs, with nasopharyngeal carcinoma (NPC) as a model cancer. The engineered commensals show specific binding to NPC via OppA-mediated recognition of surface heparan sulfate, and the loaded prodrugs are activated by tumor-associated biosignals to release SN-38, a chemotherapy compound, near NPC. In vitro experiments demonstrate that the prodrug-loaded microbes significantly increase the potency of SN-38 against NPC cell lines, up to 10-fold. In a mouse xenograft model, intravenous injection of the engineered L. plantarum leads to bacterial colonization in NPC tumors and a 67% inhibition in tumor growth, enhancing the efficacy of SN-38 by 54%.

Date: 2024
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DOI: 10.1038/s41467-024-48661-y

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