Redox Sensitive Self-Assembling Dipeptide for Sustained Intracellular Drug Delivery

Abstract

The rational design and synthesis of molecules with functional supramolecular assemblies continues to be a challenging endeavor. Self-assembled nano- and microstructures from natural building blocks are considered more appropriate for medical applications due to their biocompatible nature. We report for the first time a simple redox-responsive dipeptide that self-assembles to form vesicles in aqueous medium. The experimental results based on the control compound and all-atom molecular dynamics (MD) simulations support the mechanism of association through intermolecular π–π interactions between the indole rings of tryptophan residues. These peptide vesicles showed a DOX loading capacity of ∼16% (w/w) and redox-triggered controlled release of the packaged drug. The drug-loaded vesicles were able to penetrate into MDA-MB-231 and HeLa cells, and release payload, suggesting their putative use as chemotherapeutic delivery vehicles. These natural peptide-based carriers disassemble inside cells due to the high cytosolic GSH concentration, and the resultant Cys-Trp dipeptide is degradable. The minimalistic peptide design presented here, coupled with the propensity to form vesicles that can encapsulate the chemotherapeutic drug, opens up unlimited potential for engineering targeted sustained-release drug delivery vehicles.