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Multivalency: Key Feature in Overcoming Drug Resistance with a Cleavable Cell-Penetrating Peptide-Doxorubicin Conjugate

  • Marco Lelle
  • Christoph Freidel
  • Stefka Kaloyanova
  • Klaus Müllen
  • Kalina Peneva
Article

Abstract

Multivalency is often used in biological systems, to increase affinity and specificity through avidity. This inspired us to prepare a synthetic bioconjugate that mimics natural multivalent systems. It is composed of doxorubicin and two octaarginine cell-penetrating peptides, to strengthen the electrostatic interactions between the negatively charged glycosaminoglycans of the plasma membrane and the guanidinium groups of the arginine residues. The multivalent conjugate has improved cellular uptake and cytotoxicity, compared to a peptide-drug conjugate with only one polyarginine and as a result it can overcome drug resistance in Kelly-ADR cells. The synthetic approach and the multivalent structure reported here can be used further as model systems, to gain insight into the biological interaction of cell-penetrating peptides with artificial membranes or for the preparation of more complex multimers.

Keywords

Cell-penetrating peptide Multivalency Drug-peptide conjugate MDR Doxorubicin Drug resistance 

Notes

Acknowledgements

The authors are thankful to Dr. Alexander Schramm, Clinic for Pediatrics III, University Hospital Essen for providing the Kelly-WT and Kelly-ADR cells.

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interest.

Research Involving Human and Animal Rights

This article does not contain any studies with animals and human participants performed by any of the authors.

Supplementary material

10989_2017_9622_MOESM1_ESM.docx (1.9 mb)
Supplementary material 1 (DOCX 1908 KB)

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Max Planck Institute for Polymer ResearchMainzGermany
  2. 2.Institute of Organic and Macromolecular Chemistry, Jena Center of Soft MatterFriedrich Schiller University JenaJenaGermany
  3. 3.Institute of Physiology IIUniversity Hospital JenaJenaGermany

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