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  3. Overcoming drug resistance by cell-penetrating peptide-mediated delivery of a doxorubicin dimer with high DNA-binding affinity

Overcoming drug resistance by cell-penetrating peptide-mediated delivery of a doxorubicin dimer with high DNA-binding affinity

  • Eur J Med Chem. 2017 Apr 21:130:336-345. doi: 10.1016/j.ejmech.2017.02.056.
Marco Lelle 1,  Christoph Freidel 2,  Stefka Kaloyanova 2,  Ilja Tabujew 3,  Alexander Schramm 4,  Michael Musheev 5,  Christof Niehrs 6,  Klaus Müllen 2,  Kalina Peneva 7
Affiliations

Affiliations

  • 1 Institute of Organic Chemistry and Macromolecular Chemistry, Jena Center of Soft Matter, Friedrich Schiller University Jena, Lessingstr. 8, 07743, Jena, Germany; Institute of Physiology II, University Hospital Jena, Kollegiengasse 9, 07743, Jena, Germany; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
  • 2 Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
  • 3 Institute of Organic Chemistry and Macromolecular Chemistry, Jena Center of Soft Matter, Friedrich Schiller University Jena, Lessingstr. 8, 07743, Jena, Germany; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
  • 4 Clinic for Pediatrics III, University Hospital Essen, Hufelandstraße 55, 45122 Essen, Germany.
  • 5 Institute of Molecular Biology, Ackermannweg 4, 55128, Mainz, Germany.
  • 6 Institute of Molecular Biology, Ackermannweg 4, 55128, Mainz, Germany; Division of Molecular Embryology, DKFZ-ZMBH Alliance, 69120, Heidelberg, Germany.
  • 7 Institute of Organic Chemistry and Macromolecular Chemistry, Jena Center of Soft Matter, Friedrich Schiller University Jena, Lessingstr. 8, 07743, Jena, Germany; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany. Electronic address: kalina.peneva@uni-jena.de.
PMID: 28273560 DOI: 10.1016/j.ejmech.2017.02.056
Abstract

We describe the synthesis and characterization of a novel bioconjugate, consisting of an octaarginine cell-penetrating peptide and a highly DNA-affine doxorubicin dimer. The linkage between the two components is composed of a cleavable disulfide bond, which enables the efficient intracellular delivery of the cytotoxic payload within the reductive environment of the cytosol, mediated through glutathione. To determine the DNA-binding affinity of the dimeric drug molecule, microscale thermophoresis was applied. This is the first utilization of this method to assess the binding interactions of an anthracycline drug with nucleic acids. The cytotoxic effect of the peptide-drug conjugate, studied with drug-sensitive and doxorubicin-resistant Cancer cells, demonstrates that the bioconjugate can successfully overcome drug resistance in neuroblastoma cells.

Keywords

Cell-penetrating peptide; DNA-binding; Doxorubicin; Microscale thermophoresis; Multidrug resistance.

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