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

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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

Original languageEnglish
Article number2105506
JournalAdvanced Science
Volume9
Issue number13
Early online date4 Mar 2022
DOIs
Accepted/In press2022
E-pub ahead of print4 Mar 2022
Published5 May 2022

Bibliographical note

Funding Information: C.H.C. and A.E. were supported by KCL PhD scholarships. K.S. thanks the Leverhulme Trust for funding (ECF-2014-178). The authors are grateful to Prof. Robert Weinberg (Whitehead Institute, MIT) for providing the cell lines used in this study. J.P.U. was supported by a China 1000 Plan's Program for Young Talents (13Z127060001). The authors thank Katherine Tripp at the Center for Molecular Biophysics, Johns Hopkins University for helping the experimental setup for isothermal titration calorimeter. The authors thank the Karlsruhe Institute of Technology (KIT) ANKA synchrotron CD beamline staff for support and beamtime. The authors thank Jochen Bürck at KIT for technical support for ANKA synchrotron CD beamline. The authors thank Bing-Yu Yao and Chi-Long Lin at Academia Sinica for technical supports for nanoprecipitation and confocal microscopy, respectively. The authors thank Timothy K. Lu at Massachusetts Institute of Technology and Jing-Ruey Joanna Yeh at Massachusetts General Hospital for valuable discussions. Funding Information: C.H.C. and A.E. were supported by KCL PhD scholarships. K.S. thanks the Leverhulme Trust for funding (ECF‐2014‐178). The authors are grateful to Prof. Robert Weinberg (Whitehead Institute, MIT) for providing the cell lines used in this study. J.P.U. was supported by a China 1000 Plan's Program for Young Talents (13Z127060001). The authors thank Katherine Tripp at the Center for Molecular Biophysics, Johns Hopkins University for helping the experimental setup for isothermal titration calorimeter. The authors thank the Karlsruhe Institute of Technology (KIT) ANKA synchrotron CD beamline staff for support and beamtime. The authors thank Jochen Bürck at KIT for technical support for ANKA synchrotron CD beamline. The authors thank Bing‐Yu Yao and Chi‐Long Lin at Academia Sinica for technical supports for nanoprecipitation and confocal microscopy, respectively. The authors thank Timothy K. Lu at Massachusetts Institute of Technology and Jing‐Ruey Joanna Yeh at Massachusetts General Hospital for valuable discussions. Publisher Copyright: © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.

King's Authors

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.

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