Integrated Design of a Membrane-Lytic Peptide-Based Intravenous Nanotherapeutic Suppresses Triple-Negative Breast Cancer

Charles H. Chen, Yu Han Liu, Arvin Eskandari, Jenisha Ghimire, Leon Chien Wei Lin, Zih Syun Fang, William C. Wimley, Jakob P. Ulmschneider, Kogularamanan Suntharalingam, Che Ming Jack Hu, Martin B. Ulmschneider*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Article number2105506
JournalAdvanced Science
Volume9
Issue number13
Early online date4 Mar 2022
DOIs
Publication statusPublished - 5 May 2022

Keywords

  • anticancer peptides
  • drug resistance
  • membrane-active anticancer agents
  • multicellular tumor spheroids
  • murine models
  • nanoparticles
  • triple negative breast cancer

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