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- Title
Prodrug-conjugated tumor-seeking commensals for targeted cancer therapy.
- Authors
Shen, Haosheng; Zhang, Changyu; Li, Shengjie; Liang, Yuanmei; Lee, Li Ting; Aggarwal, Nikhil; Wun, Kwok Soon; Liu, Jing; Nadarajan, Saravanan Prabhu; Weng, Cheng; Ling, Hua; Tay, Joshua K.; Wang, De Yun; Yao, Shao Q.; Hwang, In Young; Lee, Yung Seng; Chang, Matthew Wook
- 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%. The chemotherapeutic efficacy of prodrug is limited by its cancer-targeting ability. Here this group reports an engineered commensal Lactobacillus plantarum strain with anticancer prodrugs loading on the surface for nasopharyngeal carcinoma cell-targeting and growth inhibition.
- Subjects
CANCER treatment; HEPARAN sulfate; TUMOR growth; BACTERIAL colonies; NASOPHARYNX cancer; LACTOBACILLUS plantarum; LACTIC acid bacteria
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-48661-y