Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer.
anticancer peptides
drug resistance
membrane-active anticancer agents
multicellular tumor spheroids
murine models
nanoparticles
triple negative breast cancer
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
revised:
12
01
2022
received:
29
11
2021
pubmed:
6
3
2022
medline:
7
5
2022
entrez:
5
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35246961
doi: 10.1002/advs.202105506
pmc: PMC9069370
doi:
Substances chimiques
Antineoplastic Agents
0
Peptides
0
Doxorubicin
80168379AG
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2105506Subventions
Organisme : KCL PhD scholarships
Organisme : Leverhulme Trust
Organisme : China 1000 Plan's Program for Young Talents
ID : 13Z127060001
Informations de copyright
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
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