Engineering Anticancer Amphipathic Peptide-Dendronized Compounds for Highly-Efficient Plasma/Organelle Membrane Perturbation and Multidrug Resistance Reversal.

Discovering new strategies for combating drug-resistant tumors becomes a worldwide challenge. Thereinto, stubborn drug-resistant tumor membrane is a leading obstacle on chemotherapy. Herein, we report a novel tumor-activatable amphipathic peptide-dendronized compound, which could form nanoaggregates in aqueous solutions, for perturbing tumor plasma/organelle membrane and reversing multidrug resistance. Distinguished from classical linear amphipathic peptide drugs for membrane disturbance, dendritic lysine-based architecture is designed as a multivalent scaffold to amplify the supramolecular interactions of cationic compound with drug-resistant tumor membrane. Moreover, arginine-rich residues as terminal groups are hopeful to generate multiple hydrogen bonding and electrostatic interactions with tumor membrane. On the other hand, antitumor molecule (doxorubicin) is devised as a hydrophobic moiety to intensify the membrane-inserting ability owing to the prominent interactions with hydrophobic domains of drug-resistant tumor membrane. As expected, these amphipathic peptide-dendronized compounds within the nanoaggregates could severely disturb both the structures and functions of tumor plasma/organelle membrane system, thereby resulting in the rapid leakage of many critical biomolecules, highly efficient apoptotic activation and antiapoptotic inhibition. This strategy on tumor membrane perturbation demonstrates a bran-new antitumor activity with high contributions to cell cycle arrest (at the S phase), strong apoptosis-inducing ability and satisfying cytotoxicity to a variety of drug-resistant tumor cell lines.