Mitochondria-targeting organoselenium theranostic radioprotectors for simultaneous treatment and imaging of radiation-induced liver injury.

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 H2O2 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 H2O2 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 selenium-substituted heptamethine cyanines as next-generation radioprotectors for imaging-guided therapy of other radiation-induced diseases.