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

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.