Abstract
Glutathione (GSH) is an important antioxidant that maintains cellular redox homeostasis and significantly contributes to resistance against various chemotherapeutic agents. To address the challenge of GSH-mediated drug resistance in etoposide (ETS), we developed a facile synthetic method to prepare a biocompatible acid-responsive polycarbonate (PEG-PCA) containing cinnamaldehyde (CA), a potent GSH-depleting agent, as a side chain using nontoxic raw materials. This polymer self-assembled in aqueous solutions to form nanoparticles (ETS@PCA) that encapsulated ETS, enhancing its water solubility and enabling tumor-targeted delivery. In vitro studies demonstrated that ETS@PCA could respond to the acidic tumor microenvironment, releasing CA to rapidly deplete GSH levels. Consequently, ETS@PCA exhibited superior cytotoxicity compared to free ETS. Furthermore, in vivo experiments corroborated the enhanced tumor inhibitory effects of ETS@PCA.