Histone deacetylase inhibiting nanoprodrugs for enhanced chemodynamic therapy through multistage downregulating...

The unique redox homeostasis in tumor cells makes chemodynamic therapy (CDT) a promising strategy for cancer treatment. However, high glutathione (GSH) level within tumor cells severely impacts the efficacy of CDT. Therefore, reducing intracellular GSH levels has become an approach to enhance CDT. Here, we propose a HDAC inhibiting nanoprodrug consisting of an amphiphilic reactive oxygen species (ROS)-responsive polyprodrug and a GSH-responsive dimer. The high ROS level in tumor tissues can trigger the release of cinnamaldehyde and ferrocene to upregulate intracellular ROS levels through generation of hydroxyl radicals. Additionally, the dimer can react with intracellular GSH to release histone deacetylase (HDAC) inhibitors for inhibiting HDAC, thereby suppressing GSH synthesis by reducing precursor supply. The multistage depletion of GSH can further enhance oxidative damage of hydroxyl radicals to cancer cells. This study provides a promising HDAC-inhibiting strategy to achieve GSH depletion for enhanced CDT.