Reactive oxygen species-responsive polyprodrug micelles deliver cell cycle regulators for chemosensitization

Combination chemotherapy is a common strategy to enhance treatment efficacy and avoid multidrug resistance (MDR) in clinical practice. However, it is difficult to ensure the co-enrichment and reasonable ratio of synergistic drugs in the lesion site after intravenous administration. Integrating synergistic drugs into a nanocarrier can improve drug stability, targeting, drug loading, and importantly, ensure that synergistic drugs work at one destination. This study uses 10-hydroxycamptothecin (HCPT) to construct a polymeric prodrug micelle, and the demethylcantharidin (DMC) is proportionally encapsulated within the micelle. Triggered by reactive oxygen species (ROS), HCPT and DMC were released simultaneously from the co-delivery platform in tumor cells. DMC promotes abnormal cell division by inhibiting the synthesis of the cell cycle checkpoint kinase Protein phosphatase 2A (PP2A), leading to increased cell vulnerability to DNA damage, disordered replication, and death. The co-delivery platform exhibited satisfactory biosafety and antitumor efficacy in vivo. The proposed co-delivery platform may provide a valuable reference for the translation of clinical combination chemotherapy regimens into nano-drug delivery systems.