Mitochondrion-Anchoring Photosensitizer with Aggregation-Induced Emission Characteristics Synergistically Boosts the Radiosensitivity of Cancer Cells to Ionizing Radiation

Abstract

The first mitochondrion-anchoring photosensitizer that specifically generates singlet oxygen (¹ O₂ ) in mitochondria under white light irradiation that can serve as a highly effective radiosensitizer is reported here, significantly sensitizing cancer cells to ionizing radiation. An aggregation-induced emission luminogen (AIEgen), namely DPA-SCP, is rationally designed with α-cyanostilbene as a simple building block to reveal AIE, diphenylamino (DPA) group as a strong electron donating group to benefit red emission and efficient light-controlled ¹ O₂ generation, as well as a pyridinium salt as the targeting moiety to ensure specific mitochondrial localization. The AIE signature endows DPA-SCP with the capacity to visualize mitochondria in a fluorescence turn-on mode. It is found that under optimized experimental condition, DPA-SCP with white light does not lead to apoptosis/death of cancer cells, whereas provides an elevated ¹ O₂ environment in the mitochondria. More importantly, increasing intracellular level of ¹ O₂ originated from mitochondria is demonstrated to be a generic method to enhance the radiosensitivity of cancer cells with a supra-additive synergistic effect of "0 + 1 > 1." Noteworthy is that "DPA-SCP + white light" achieves a high SER10 value of 1.62, which is much larger than that of the most popularly used radiosensitizers, gold nanoparticles (1.19), and paclitaxel (1.32).

Keywords: aggregation-induced emission; mitochondrial targeting; photosensitizer; radiation therapy; radiosensitization.