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Covalent cell surface recruitment of chemotherapeutic polymers enhances selectivity and activity
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Tomás, Ruben M. F. and Gibson, Matthew I. (2021) Covalent cell surface recruitment of chemotherapeutic polymers enhances selectivity and activity. Chemical Science, 12 (12). pp. 4557-4569. doi:10.1039/D0SC06580C ISSN 2041-6520.
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Official URL: https://doi.org/10.1039/D0SC06580C
Abstract
Synthetic macromolecular chemotherapeutics inspired by host defence peptides can disrupt cell membranes and are emerging as agents for the treatment of cancer and infections. However, their off-target effects remain a major unmet challenge. Here we introduce a covalent recruitment strategy, whereby metabolic oligosaccharide engineering is used to label targeted cells with azido glycans, to subsequently capture chemotherapeutic polymers by a bio-orthogonal click reaction. This results in up to 10-fold reduction in EC50 and widening of the therapeutic window. Cell death is induced by not only membrane leakage, but also by apoptosis due to the conjugated chemotherapeutic being internalised by glycan recycling. Covalent recruitment also lead to increased penetration and significant cell death in a 3-D tumour model in just 3 hours, whereas doxorubicin required 24 hours. This conceptual approach of ‘engineering cells to capture polymers’ rather than ‘engineering polymers to target cells’ will bring new opportunities in non-traditional macromolecular therapeutics.
Item Type: | Journal Article | |||||||||
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Subjects: | Q Science > QH Natural history Q Science > QP Physiology Q Science > QR Microbiology R Medicine > RS Pharmacy and materia medica |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | |||||||||
SWORD Depositor: | Library Publications Router | |||||||||
Library of Congress Subject Headings (LCSH): | Drug resistance in cancer cells, Oligosaccharides, Cell membranes, Peptide antibiotics | |||||||||
Journal or Publication Title: | Chemical Science | |||||||||
Publisher: | Royal Society of Chemistry | |||||||||
ISSN: | 2041-6520 | |||||||||
Official Date: | 28 March 2021 | |||||||||
Dates: |
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Volume: | 12 | |||||||||
Number: | 12 | |||||||||
Page Range: | pp. 4557-4569 | |||||||||
DOI: | 10.1039/D0SC06580C | |||||||||
Status: | Peer Reviewed | |||||||||
Publication Status: | Published | |||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||
Date of first compliant deposit: | 8 March 2021 | |||||||||
Date of first compliant Open Access: | 9 March 2021 | |||||||||
RIOXX Funder/Project Grant: |
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