Mitochondria-Targeting and ROS-Cleavable Hemicyanine-Tranexamic Acid Conjugates as Radioprotective Agents Mitigated Radiation-Induced Skin Injury.

Radiation-induced skin injury (RISI) is one of the most common illnesses in external beam radiotherapy. Although some commercial drugs for external use have been developed to prevent and alleviate RISI, a majority of them usually adopt a single chemical repair pathway by scavenging intracellular toxic reactive oxygen species (ROS) with limited treatment outcomes. Particularly, the therapeutic effect toward high-dosage acute radiation injury remains unsatisfactory in the clinic. Mitochondria play vital roles not only as cellular energy factories but also as the main organelles to produce intracellular ROS and maintain the balance of oxidation stress and inflammation. Thus, targeting the protection of mitochondria from radiation-induced damage may effectively improve RISI treatment. Herein, in this work, we designed and reported a series of mitochondria-targeting radioprotective hemicyanine (HCY) small molecules to treat acute RISI synergistically by antioxidation, anti-inflammation, and plasminogen inhibition for wound healing. Using ROS-cleavable enamine bonds, different mitochondria-targeting structures of HCY were chemically conjugated with tranexamic acid (TA), a plasminogen inhibitor previously reported for attenuating RISI by the regulation of mitochondrial function. Thus, the specific delivery and release of TA in mitochondria were achieved to enhance RISI treatment and minimize the side effect. Our findings in this work not only demonstrate a promising potential of HCY-TA conjugates for RISI treatment but also propose an innovative mitochondria-targeting delivery system to hopefully mitigate radiation-induced other diseases.