title: Overcoming drug resistance by cell-penetrating peptide-mediated delivery of a doxorubicin dimer with high DNA-binding affinity.
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.
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Lelle
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Freidel
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
authors.forename: Stefka
authors.initials: S
authors.lastname: Kaloyanova
authors.affiliation: 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.
authors.forename: Ilja
authors.initials: I
authors.lastname: Tabujew
authors.affiliation: Clinic for Pediatrics III, University Hospital Essen, Hufelandstraße 55, 45122 Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.affiliation: Institute of Molecular Biology, Ackermannweg 4, 55128, Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Musheev
authors.affiliation: Institute of Molecular Biology, Ackermannweg 4, 55128, Mainz, Germany; Division of Molecular Embryology, DKFZ-ZMBH Alliance, 69120, Heidelberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Niehrs
authors.affiliation: Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Müllen
authors.affiliation: 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.
authors.forename: Kalina
authors.initials: K
authors.lastname: Peneva
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D018736:DNA Adducts / Q000737:chemistry; D019281:Dimerization; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D057846:Cell-Penetrating Peptides; D018736:DNA Adducts; D009842:Oligopeptides; C031902:doxorubicin-DNA; C448619:octaarginine; D004317:Doxorubicin
keywords: Cell-penetrating peptide; DNA-binding; Doxorubicin; Microscale thermophoresis; Multidrug resistance