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Targeting a c-Myc inhibitory polypeptide to specific intracellular compartments using cell penetrating peptides.

Abstract
The therapeutic index of current anti-cancer chemotherapeutics can be improved by two major mechanisms: 1) developing drugs which are specifically toxic to the cancer cells and 2) developing methods to deliver drugs to the tumor site. In an attempt to combine these approaches, we developed a thermally responsive polypeptide inhibitor of c-Myc. This polypeptide is based on the thermally responsive Elastin-like polypeptide (ELP). When injected systemically, ELP-fused drugs will aggregate and accumulate at the tumor site where local hyperthermia is applied. ELP was fused to a peptide which blocks c-Myc/Max dimerization (H1), thereby inhibiting transcription activation by c-Myc (ELP-H1). In this study, the cellular uptake, intracellular distribution, and potency of the Pen, Tat and Bac cell penetrating peptides fused to ELP-H1 were evaluated. While Pen-ELP-H1 and Tat-ELP-H1 were localized in the cytoplasm, Bac-ELP-H1 localized to the nucleus in a subset of the cells and was the most potent inhibitor of MCF-7 cell proliferation. This data demonstrates that ELP can be targeted to the desired cellular compartment simply by choice of the CPP used, resulting in a more potent nuclear targeted c-Myc inhibitory polypeptide which may be beneficial in cancer therapy.
AuthorsGene L Bidwell 3rd, Aisha N Davis, Drazen Raucher
JournalJournal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 135 Issue 1 Pg. 2-10 (Apr 02 2009) ISSN: 1873-4995 [Electronic] Netherlands
PMID19095020 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Drug Carriers
  • MYC protein, human
  • Peptide Fragments
  • Peptides
  • Proto-Oncogene Proteins c-myc
  • Recombinant Fusion Proteins
  • elastin polypentapeptide
Topics
  • Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology)
  • Cell Line, Tumor
  • Cell Nucleus (drug effects, metabolism)
  • Cell Proliferation (drug effects)
  • Cytoplasm (drug effects, metabolism)
  • Dose-Response Relationship, Drug
  • Drug Carriers (chemical synthesis, chemistry, pharmacokinetics)
  • Female
  • Humans
  • Hyperthermia, Induced
  • Microscopy, Fluorescence
  • Neoplasms (drug therapy, metabolism)
  • Peptide Fragments (chemical synthesis, chemistry, pharmacokinetics)
  • Peptides (chemical synthesis, chemistry, pharmacokinetics)
  • Phase Transition
  • Proto-Oncogene Proteins c-myc (antagonists & inhibitors)
  • Recombinant Fusion Proteins (chemical synthesis, chemistry, pharmacokinetics)
  • Temperature
  • Time Factors

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