1. Selective activation of prodrugs in breast cancer using metabolic glycoengineering and the tetrazine ligation bioorthogonal reaction.
- Author
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Mitry MMA, Dallas ML, Boateng SY, Greco F, and Osborn HMI
- Subjects
- Humans, Female, Molecular Structure, Drug Screening Assays, Antitumor, Structure-Activity Relationship, MCF-7 Cells, Dose-Response Relationship, Drug, Cell Proliferation drug effects, Metabolic Engineering, Cell Survival drug effects, Prodrugs chemistry, Prodrugs pharmacology, Prodrugs chemical synthesis, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis
- Abstract
Increasing the selectivity of chemotherapies by converting them into prodrugs that can be activated at the tumour site decreases their side effects and allows discrimination between cancerous and non-cancerous cells. Herein, the use of metabolic glycoengineering (MGE) to selectively label MCF-7 breast cancer cells with tetrazine (Tz) activators for subsequent activation of prodrugs containing the trans-cyclooctene (TCO) moiety by a bioorthogonal reaction is demonstrated. Three novel Tz-modified monosaccharides, Ac
4 ManNTz 7, Ac4 GalNTz 8, and Ac4 SiaTz 16, were used for expression of the Tz activator within sialic-acid rich breast cancer cells' surface glycans through MGE. Tz expression on breast cancer cells (MCF-7) was evaluated versus the non-cancerous L929 fibroblasts showing a concentration-dependant effect and excellent selectivity with ≥35-fold Tz expression on the MCF-7 cells versus the non-cancerous L929 fibroblasts. Next, a novel TCO-N-mustard prodrug and a TCO-doxorubicin prodrug were analyzed in vitro on the Tz-bioengineered cells to probe our hypothesis that these could be activated via a bioorthogonal reaction. Selective prodrug activation and restoration of cytotoxicity were demonstrated for the MCF-7 breast cancer cells versus the non-cancerous L929 cells. Restoration of the parent drug's cytotoxicity was shown to be dependent on the level of Tz expression where the Ac4 ManNTz 7 and Ac4 GalNTz 8 derivatives (20 µM) lead to the highest Tz expression and full restoration of the parent drug's cytotoxicity. This work suggests the feasibility of combining MGE and tetrazine ligation for selective prodrug activation in breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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