Evodiamine-Based Nitroreductase Responsive Theranostic Agents for Treatment of Colon Cancer

Hypoxia is a state of low oxygen tension that is found in numerous solid tumors. Generally, nitroreductase (NTR) is overexpressed and directly correlated with the hypoxic status in solid tumors, supporting the hypothesis that prodrug could be activated by intracellular NTR and lead to potential antitumor therapy. Herein, evodiamine-based hypoxia-targeting theranostic agents were developed to enhance the antitumor efficacy. These agents are activated by NTR-mediated <i>p</i>-nitrobenzyl reduction, enabling simultaneous fluorophore activation for imaging and therapeutic agent (3-fluoro-10-hydroxyl-evodiamine) release for solid tumor treatment. After a systemic test, these theranostic agents were verified to be selectively activated by NTR with excellent fluorescence properties and antitumor potency. In particular, <b>Probe-2</b> exhibited excellent <i>in vivo</i> antitumor activity (tumor growth inhibition value (TGI) = 76.1%) in HCT116 xenograft nude mice with favorable tumor-targeted properties and low toxicity. Thus, this NTR-responsive theranostic agent provides a platform for constructing prodrugs to release monitoring and active substances controlled by the hypoxic status.