Glutathione-adaptive peptide amphiphile vesicles rationally designed using positionable disulfide-bridges for effective drug transport

Abstract

We report the glutathione-triggered release of an anticancer drug from vesicles constructed with peptide amphiphiles (PAs) containing a cell-penetrating TAT peptide synthesized by varying the position and number of disulfide-linkages in the PAs. PAs 1 and 2, based on random-coil structures that enable large amounts of drug loading, showed different self-assembled aggregates. These included vesicles and two-dimensional sheets as functions of the cysteine (C) position in the PA, despite the use of the same chemical building blocks. However, the formation of C-C disulfide-bridges between neighboring PAs by sonication in polar-aprotic solvent, dimethylformamide led to morphological changes into the vesicles. Interestingly, the PA vesicles demonstrated markedly different drug loading capacities and efficiencies as functions of the disulfide position during assembly. Increases in the number of disulfide formations between PAs (1-1) allowed the vesicular drug transporter to exhibit sustained anticancer-drug release to specific tumors. As all vesicles reported in this study exhibited a superior ability to deliver anticancer drugs to certain cancer cells alone, this research, which provides a biocompatible peptide design for the synthesis of efficient drug-delivery vehicles, can serve as a solid foundation for further nanocarrier developments for biomedical applications.