Bioorthogonal activation of prodrugs, for the potential treatment of breast cancer, using the Staudinger reaction

Mitry, M. M.A., Boateng, S. Y., Greco, F. and Osborn, H. M. I. ORCID: https://orcid.org/0000-0002-0683-0457 (2023) Bioorthogonal activation of prodrugs, for the potential treatment of breast cancer, using the Staudinger reaction. RSC Medicinal Chemistry, 14 (8). pp. 1537-1548. ISSN 2632-8682 doi: 10.1039/D3MD00137G

Abstract/Summary

Selective prodrug activation at a tumor site is crucial to maximise the efficiency of chemotherapy approaches and minimise side effects due to off-site activation. In this paper, a new prodrug activation strategy is reported based on the bioorthogonal Staudinger reaction. The feasibility of this prodrug activation strategy was initially demonstrated using 9-azido sialic acid 4 as a trigger and two novel triphenylphosphine-modified N-mustard-PRO 10 and doxorubicin-PRO 12 prodrugs in an HPLC-monitored release study. Then, the azide reporter group was introduced on cancer cells' surfaces through metabolic glycoengineering of sialic acid-rich surface glycans using azide-modified monosaccharides (9-azido sialic acid 4, tetra-O-acetylated-9-azido sialic acid 5 and tetra-O-acetyl azidomannosamine). Next, the N-mustard-PRO 10 and doxorubicin-PRO 12 prodrugs were employed in vitro with the bioengineered cells, and activation of the prodrugs, which allowed selective release of the cytotoxic moiety at the tumour cell, was assessed. Release of the parent drugs from the prodrugs was shown to be dependent on the level of metabolic labelling, where tetra-O-acetyl azidomannosamine allowed the highest level of azide reporter generation in tumor cells and led to full recovery of the parent cytotoxic drug's potency. The selectivity of azide expression on breast cancer MCF-7 cells versus normal fibroblast L929 cells was also probed, with the 9-azido sialic acid and tetra-O-acetylated-9-azido sialic acid showing ∼17-fold higher azide expression on the former. Taken together, these data demonstrate the feasibility of the Staudinger reaction for selective activation of prodrugs targeted to the MCF-7 breast cancer cells.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/112199
Identification Number/DOI	10.1039/D3MD00137G
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Chemical Analysis Facility (CAF) Life Sciences > School of Biological Sciences > Biomedical Sciences Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Medicinal Chemistry Research Group Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Pharmaceutics Research Group
Publisher	Royal Society of Chemistry
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