A smart cascade theranostic prodrug system activated by hydrogen peroxide for podophyllotoxin delivery

The construction of selectively activated prodrugs serves as a crucial strategy for reducing the adverse effects associated with disease treatment. Cascade self-assembled visual prodrugs have been applied to the construction of selective activated prodrugs with low background interference and in situ fluorescence. In this work, we rationally designed an anticancer theranostic prodrug (CM-PPT) consisting of an anticancer drug podophyllotoxin, a fluorescent dye precursor, and an H₂O₂ trigger boronate ester group, which could be activated by H₂O₂ oxidation, thereby releasing active anticancer molecules and forming fluorescent fragments concurrently. In vitro experiments revealed that the prodrug has potent anticancer efficacy, and the drug release rate could be visualized by the fluorescence intensity. In addition, intraperitoneal administration of the prodrug to mice demonstrated outstanding antitumor activities. Thus, this design of H₂O₂-responsive prodrug may provide a promising strategy for selective imaging of H₂O₂ status, real-time tracking of drug release, and personalized tumor treatment.