Internalization of p53(14-29) peptide amphiphiles and subsequent endosomal disruption results in SJSA-1 cell death.
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 p53(14-29) 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.
Missirlis
Dimitris
D
Department of Chemical Engineering, University of California, Santa Barbara, California 93106, USA. dimis@berkeley.edu
Krogstad
Daniel V
DV
Tirrell
Matthew
M
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D011992:Endosomes / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry / Q000494:pharmacology; D008823:Micelles; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry; D010316:Particle Size; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D046911:Macromolecular Substances; D008823:Micelles; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53
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