Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer.
Authors
Chen, Charles H
Liu, Yu-Han
Eskandari, Arvin
Ghimire, Jenisha
Lin, Leon Chien-Wei
Fang, Zih-Syun
Wimley, William C
Ulmschneider, Jakob P
Suntharalingam, Kogularamanan
Hu, Che-Ming Jack
Publication Date
2022-05Journal Title
Adv Sci (Weinh)
ISSN
2198-3844
Publisher
Wiley
Language
en
Type
Article
This Version
AO
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Chen, C. H., Liu, Y., Eskandari, A., Ghimire, J., Lin, L. C., Fang, Z., Wimley, W. C., et al. (2022). Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer.. Adv Sci (Weinh) https://doi.org/10.1002/advs.202105506
Description
Funder: KCL PhD scholarships
Funder: Leverhulme Trust; Id: http://dx.doi.org/10.13039/501100000275
Abstract
Membrane-lytic peptides offer broad synthetic flexibilities and design potential to the arsenal of anticancer therapeutics, which can be limited by cytotoxicity to noncancerous cells and induction of drug resistance via stress-induced mutagenesis. Despite continued research efforts on membrane-perforating peptides for antimicrobial applications, success in anticancer peptide therapeutics remains elusive given the muted distinction between cancerous and normal cell membranes and the challenge of peptide degradation and neutralization upon intravenous delivery. Using triple-negative breast cancer as a model, the authors report the development of a new class of anticancer peptides. Through function-conserving mutations, the authors achieved cancer cell selective membrane perforation, with leads exhibiting a 200-fold selectivity over non-cancerogenic cells and superior cytotoxicity over doxorubicin against breast cancer tumorspheres. Upon continuous exposure to the anticancer peptides at growth-arresting concentrations, cancer cells do not exhibit resistance phenotype, frequently observed under chemotherapeutic treatment. The authors further demonstrate efficient encapsulation of the anticancer peptides in 20 nm polymeric nanocarriers, which possess high tolerability and lead to effective tumor growth inhibition in a mouse model of MDA-MB-231 triple-negative breast cancer. This work demonstrates a multidisciplinary approach for enabling translationally relevant membrane-lytic peptides in oncology, opening up a vast chemical repertoire to the arms race against cancer.
Keywords
Research Article, Research Articles, anticancer peptides, drug resistance, membrane‐active anticancer agents, multicellular tumor spheroids, murine models, nanoparticles, triple negative breast cancer
Sponsorship
China 1000 Plan's Program for Young Talents (13Z127060001)
Identifiers
advs3581
External DOI: https://doi.org/10.1002/advs.202105506
This record's URL: https://www.repository.cam.ac.uk/handle/1810/334694
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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