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Internalization of p53(14-29) peptide amphiphiles and subsequent endosomal disruption results in SJSA-1 cell death

Dimitris Missirlis1, Daniel V Krogstad, Matthew Tirrell

  • 1Department of Chemical Engineering, University of California, Santa Barbara, California 93106, USA. dimis@berkeley.edu

Molecular Pharmaceutics
|September 9, 2010
PubMed

Insights

Hydrophobic modification of peptides enhances intracellular delivery, enabling peptide amphiphiles to self-assemble into nanoparticles. This strategy overcomes delivery challenges for potential cancer therapeutics targeting the p53-MDM2 interaction.

Area of Science:

  • Biochemistry
  • Nanotechnology
  • Molecular Biology

Background:

  • Inhibition of the tumor suppressor p53-MDM2 interaction is a therapeutic strategy for cancer.
  • Efficient intracellular delivery of inhibitory peptides remains a significant challenge.

Purpose of the Study:

  • To develop a method for enhancing the intracellular delivery of peptides targeting the p53-MDM2 interaction.
  • To investigate the self-assembly and cellular uptake mechanisms of modified peptides.

Main Methods:

  • Hydrophobic lipid-like tails were coupled to the inhibitory peptide p53(14-29) to create peptide amphiphiles.
  • Supramolecular self-assembly into wormlike micelles was characterized.
  • Cellular internalization via clathrin-mediated endocytosis and cell death induction were assessed in vitro.

Main Results:

  • Peptide amphiphiles demonstrated efficient intracellular delivery across various cell lines.
  • Self-assembled structures (wormlike micelles) facilitated peptide internalization upon disassembly.
  • Hypertonic treatment induced cell death in SJSA-1 cells treated with peptide amphiphiles.

Conclusions:

  • Hydrophobic modification is a viable strategy for improving the delivery of impermeable peptides.
  • Peptide amphiphiles can self-assemble into nanoparticles for therapeutic applications.
  • This approach offers a basis for developing novel supramolecular nanotherapeutics.

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