Radiosensitization With Nanoparticles Targeting to Mitochondria

Abstract

Sensitizing radiation therapy (RT) for cancer is highly desired to reduce side-effect of the harsh dose of irradiation, and nanoparticles with high atomic number elements provide a promising tool. However, insufficient knowledge on utilizing the interaction between nanoparticles and cancerous cells hampers the improvement of therapeutic outcome. We herein employed NaGdF4:Yb,Er nanocrystals as the sensitizer, and modified them with a tumor targeting agent and a mitochondria targeting moiety, separately and jointly, to achieve varied extent of mitochondrial accumulation. We observed that NaGdF4:Yb,Er nanocrystal, even unmodified with targeting ligands, is effective for radiosensitization. Furthermore, the extent of mitochondrial targeting was responsible for sensitization efficiency both in vitro and in vivo. By RNA sequencing (RNA-seq) technique, the result was ascribed to the reactive oxygen species (ROS) mediated TNF-JNK pathway and cell cycle arrest, rather than breaking DNA with those untargeted nanoparticles. Our work indicated that ROS generated by the irradiation can be utilized by activating an alternative apoptotic pathway with mitochondrial targeting nanoparticles, and therefore may suggest an approach for the enhancement of radiosensitization.