Disulfide/α-Amide-Bridged Doxorubicin Dimeric Prodrug: Effect of Aggregation Structures on pH/GSH Dual-Triggered Drug Release

Disulfide bonding has attracted intense interest in the tumor intracellular microenvironment-activated drug delivery systems (DDSs) in the last decades. Although various molecular structures of redox-responsive disulfide-containing DDSs have been developed, no investigation was reported on the effect of aggregation structures. Here, the effect of aggregation structures on pH/GSH dual-triggered drug release was investigated with the simplest pH/GSH dual-triggered doxorubicin-based drug self-delivery system (DSDS), the disulfide/α-amide-bridged doxorubicin dimeric prodrug (DDOX), as a model. By fast precipitation or slow self-assembly, DDOX nanoparticles were obtained. With similar diameters, they exhibited different pH/GSH dual-triggered drug releases, demonstrating the effect of aggregation structures. The π–π stacking in different degrees was revealed by the UV–vis, fluorescence, and BET analysis of the DDOX nanoparticles. The effect of the π–π stacking between the dimeric prodrug and its activated products on drug release was also explored with the molecular simulation approach. The finding opens new ideas in the design of high-performance DDSs for future precise tumor treatment.