Intelligent Design of Artesunate-like Analogue Nanoassemblies for Optimized Antitumor Efficacy

Artemisinin derivatives show antitumor potential via their peroxide bridge, but dihydroartemisinin (DHA) suffers from poor solubility and limited targeting. In this study, inspired by artesunate (ART), we synthesized two derivatives, DHA-CC and DHA-SS, and prepared their PEGylated nanoassemblies (pNAs) using DSPE-PEG 2K to enhance their in vivo stability and prolong circulation. Between the two derivatives, DHA-SS pNAs, with their unique disulfide bond structure, demonstrated superior stability, circulation time, and tumor accumulation. Importantly, DHA-SS pNAs exhibited specific responsive drug release under the reductive tumor microenvironment (TME), thereby achieving a favorable balance between systemic stability and efficient activation at the tumor site. In vitro and in vivo evaluations demonstrated that DHA-SS pNAs have higher reactive oxygen species (ROS) generation, greater cytotoxicity, and enhanced antitumor effects without evident systemic toxicity. Overall, these findings demonstrate that this rational structural modification offers a promising strategy for advancing artemisinin-based antitumor therapies toward clinical translation.