Harnessing the Power of a H2O2-Activated Theranostic Probe against Doxorubicin-Induced Cardiotoxicity.

Doxorubicin (Dox) is a highly effective antitumor drug with established therapeutic benefits across various tumor types, whose non-negligible and potent side effect is the Dox-induced cardiotoxicity (DIC). Early diagnosis of DIC is difficult, and available therapeutic regimens are quite limited. Inspired by the unique structure and efficient anti-DIC bioactivity of the natural compound tanshinone IIA (Tan IIA), we rationally developed its fluorescently emissive analogue TOP with preserved anti-DIC efficacy. Especially, TOP was fabricated into a hydrogen peroxide (H2O2)-responsive prodrug TOP-B, which could be activated by the oxidation stress during DIC, thereby facilitating the simultaneous fluorescence monitoring and treatment of DIC. Specifically, monitoring the fluctuation of H2O2 with the probe TOP-B can directly reflect the progression of DIC in the cardiomyocyte, zebrafish, and mouse models. TOP-B can also promote the expression of antioxidant proteins, which contribute to the alleviation of DIC. Needless to say, probe TOP-B not only serves as a promising therapeutic drug and fluorescence-guided imaging agent for DIC, but more importantly provides inspiration to construct other rationally designed theranostic probes derived from the natural product skeletons for specific diseases.