Internalization of p5314-29 peptide amphiphiles and subsequent endosomal disruption results in SJSA-1 cell death

Dimitris Missirlis, Daniel V. Krogstad, Matthew Tirrell

Research output: Contribution to journalArticle

Abstract

In vivo peptide inhibition of tumor suppressor p53 binding to the protein MDM2 is hampered by inefficient delivery of the peptide. Our approach to couple a hydrophobic lipid-like tail on the inhibitory peptide p5314-29 allowed its intracellular delivery in vitro, in a panel of different cell lines. The constructed chimeric molecules, termed peptide amphiphiles, further self-assembled into supramolecular structures, identified as elongated wormlike micelles. Internalization of peptides occurred following micelle disassembly, partly via clathrin-mediated endocytosis of monomers. Incubation of SJSA-1 cells in hypertonic culture media, aimed to disrupt endocytic vesicles, resulted in peptide amphiphile-mediated cell death. Our results provide the basis for the construction of novel therapeutic supramolecular nanoparticles and suggest hydrophobic modification of peptides as a promising strategy for enhancing delivery of impermeable peptides.

Original languageEnglish (US)
Pages (from-to)2173-2184
Number of pages12
JournalMolecular pharmaceutics
Volume7
Issue number6
DOIs
StatePublished - Dec 6 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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