Facile synthesis of an acid-responsive cinnamaldehyde-pendant polycarbonate for enhancing the anticancer efficacy of etoposide via glutathione depletion

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.