Multivalency: Key Feature in Overcoming Drug Resistance with a Cleavable Cell-Penetrating Peptide-Doxorubicin Conjugate
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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.
KeywordsCell-penetrating peptide Multivalency Drug-peptide conjugate MDR Doxorubicin Drug resistance
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.
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