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ECM-targeting bacteria enhance chemotherapeutic drug efficacy by lowering IFP in tumor mouse models
Abstract
Bacterial cancer therapies aim to manipulate bacteria to effectively deploy therapeutic payloads to tumors. Attenuated bacteria alone often cannot eradicate solid tumors. Attenuated Salmonella can be engineered to deliver cytotoxic drugs to either trigger an immune response or increase antitumor efficacy when combined with chemotherapeutic drugs. However, the extracellular matrix (ECM) surrounding cancer cells forms a barrier that often limits the ability of chemotherapeutic and cytotoxic drugs to penetrate and eliminate tumors. To overcome this limitation, we developed a strategy to combine chemotherapy with an attenuated Salmonella typhimurium strain engineered to secrete HysA protein (from Staphylococcus aureus; Hyaluronidase, HAase) in tumors. The engineered Salmonella effectively degraded hyaluronan (HA), which is a major ECM constituent in tumors, and suppressed tumor growth in mouse models of pancreatic adenocarcinoma (ASPC-1) and breast cancer (4T1). Furthermore, it prolonged survival when combined with chemotherapeutic drugs (doxorubicin or gemcitabine). Upon bacterial colonization, the HAase-mediated ECM degradation decreased interstitial fluid pressure (IFP) in the tumor microenvironment. Additionally, HA degradation using HAase-expressing bacteria in vivo led to decreased binding to the receptor, CD44, expressed in tumors. This may modulate proliferation- and apoptosis-related signal pathways. Therefore, ECM-targeting bacteria can be used as a synergistic anticanc…
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“Engineered bacteria that secrete hyaluronidase degrade hyaluronan in situ, reduce interstitial fluid pressure, and potentiate chemotherapy in breast and pancreatic tumor models with survival extension [69].”
From Overcoming tumor microenvironment barriers: transformable and bioinspired nanomedicine strategies for deep tumor penetration (2026) · cites this paper as [69]
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Metadata
- Authors
- Kim, J.-S., Park, J.-E., Choi, S.-H., Kang, S. W., Lee, J. H., Lee, J.-S., Shin, M., & Park, S.-H.
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 355
- Pages
- 199-210
- ISSN
- 0168-3659
- Cited by
- 61
- References
- 3
- Language
- en
- Licence
- Funders
- Ministry of Science, ICT and Future Planning (NRF-2021M3H9A1037439, NRF-2014M3A9B5073747)
- National Research Foundation of Korea
- Korea Research Institute of Bioscience and Biotechnology (KGM5232221, NTIS1711170602)
- Korea Ministry of Trade Industry and Energy (20009412)
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