Selenium-containing metallodrug overcomes cervical cancer radioresistance through physical–chemical dual sensitization

Abstract

Radiotherapy is an important treatment for cervical cancer, but the efficacy of radiotherapy is often reduced in clinical practice owing to high frequency and high dose radiation leading to radiotherapy resistance. The development of efficient and low-toxicity radiotherapy sensitizers to reduce radiation dose is an effective strategy. Therefore, based on the existing radiotherapy sensitizers responding to radiophysical sensitization radiotherapy, we propose to design radiotherapy sensitizers with enzyme-mimicking and dual physical–chemical sensitization properties. In this work, we constructed Ru–Se complexes with cytochrome P450 enzyme-mimicking properties. On the one hand, the high concentration of ROS in tumor cells, along with the complexes, catalyzed the oxidation of intracellular active substances, breaking the redox balance of the cells and chemically sensitizing radiotherapy; on the other hand, the high atomic numbers of ruthenium and selenium responded to X-rays and physically sensitized radiotherapy. Experimental results demonstrated that the Ru–Se complexes can efficiently mimic cytochrome P450 enzyme activity and simultaneously respond to radiation dual sensitization radiotherapy, causing the expression of intracellular DNA damage response proteins. Thus, inhibition of repair protein expression overcomes radiotherapy resistance. This work provides a new idea for the development of efficient radiation sensitizers in the future.