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

Abstract

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.

• Authors: Xiao Zhang, Yachao Li, Cheng Hu, Yahui Wu, Dan Zhong, Xianghui Xu, Zhongwei Gu
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 10 Issue 37 Pg. 30952-30962 (Sep 19 2018) ISSN: 1944-8252 [Electronic] United States
• PMID: 30088909 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Peptides
• Doxorubicin

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Membrane (drug effects)
• Chemical Engineering
• Doxorubicin (pharmacology)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Organelles (drug effects)
• Peptides (chemistry, pharmacology)