Abstract

Rationale Normal liver tissue is vulnerable towards ionizing radiation, which leads to radiation-induced liver injury (RILI) and remains a clinical challenge for treatment. Due to poor tissue targeting, mostly radioprotectors show limited radioprotective effect with a narrow therapeutic window. In this study, we report a series of selenium-substituted heptamethine cyanine derivatives (Se-Cys) as versatile radioprotectors for liver-preferential accumulation, simultaneous RILI imaging and treatment. Methods A series of lipophilic cationic Se-Cys were developed with tunable properties for targeted delivery to liver mitochondria. We evaluated their deselenization kinetics in response to H 2 O 2 and investigated the downstream activation of the Keap1-Nrf2-HO-1 antioxidant axis. Specifically, the derivative Se-Cy4 was assessed for its ROS-responsive fluorescence changes. In vivo experiments were conducted to evaluate the dual capacity of Se-Cy4 for dynamic imaging and therapeutic protection against RILI, including systemic toxicity. Results The targeting delivery and ROS-responsive selenium release, significantly enhance selenium levels in injured livers and mitochondria induced by ionizing radiation. Deselenization releases bioavailable selenium from Se-Cys, elevates selenoprotein expression and exerts endogenous radioprotective effect by activating the Keap1-Nrf2-HO-1 antioxidant axis. More interestingly, Se-Cys derivatives, especially Se-Cy4, possess a sensitive fluorescent enhancement in H 2 O 2 concentration-dependent manner, offering a potential application for dynamic monitoring of ROS level in RILI. The in vivo results verify that Se-Cy4 has capacities to sensitive fluorescent imaging and efficient treatment of RILI without detectable systemic toxicity. Conclusions Se-Cy4 serves as a novel theranostic agent for RILI, by providing ROS monitoring and robust radioprotection without detectable systemic toxicity. Our findings may also promise a potential of