Manipulating the pH response of 2,3-diaminopropionic acid rich peptides to mediate highly effective gene silencing with low-toxicity

Vincenzo Abbate, Wanling Liang, Jayneil Patel, Yun Lan, Luigi Capriotti, Valentina Iacobucci, Tam T. Bui, Poulami Chaudhuri, Laila Kudsiova, Louic S. Vermeer, Patrick F.L. Chan, Xiaole Kong, Alex F. Drake, Jenny K.W. Lam, Sukhvinder S. Bansal, A. James Mason

Research output: Contribution to journalArticle

Abstract

Cationic amphipathic pH responsive peptides possess high in vitro and in vivo nucleic acid delivery capabilities and function by forming a non-covalent complex with cargo, protecting it from nucleases, facilitating uptake via endocytosis and responding to endosomal acidification by being released from the complex and inserting into and disordering endosomal membranes. We have designed and synthesised peptides to show how Coulombic interactions between ionizable 2,3-diaminopropionic acid (Dap) side chains can be manipulated to tune the functional pH response of the peptides to afford optimal nucleic acid transfer and have modified the hydrogen bonding capabilities of the Dap side chains in order to reduce cytotoxicity. When compared with benchmark delivery compounds, the peptides are shown to have low toxicity and are highly effective at mediating gene silencing in adherent MCF-7 and A549 cell lines, primary human umbilical vein endothelial cells and both differentiated macrophage-like and suspension monocyte-like THP-1 cells.
Original languageEnglish
Pages (from-to)929-938
Number of pages10
JournalJournal of Controlled Release
Volume172
Issue number3
DOIs
Publication statusPublished - 18 Oct 2013

Bibliographical note

© 2013 The Authors. Published by Elsevier B.V. Open Access under CC BY license

Keywords

  • pH responsive peptides
  • Endocytosissi
  • RNA delivery
  • Monocytes
  • Manipulation of pH response

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    Abbate, V., Liang, W., Patel, J., Lan, Y., Capriotti, L., Iacobucci, V., Bui, T. T., Chaudhuri, P., Kudsiova, L., Vermeer, L. S., Chan, P. F. L., Kong, X., Drake, A. F., Lam, J. K. W., Bansal, S. S., & Mason, A. J. (2013). Manipulating the pH response of 2,3-diaminopropionic acid rich peptides to mediate highly effective gene silencing with low-toxicity. Journal of Controlled Release, 172(3), 929-938. https://doi.org/10.1016/j.jconrel.2013.09.033