Yi Zhang,1 Dang Liu,2 Bin Qiao,3 Yuanli Luo,3 Liang Zhang,3 Yang Cao,3 Haitao Ran,3,* Chao Yang4,* 

1Department of Ultrasound, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Radiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 3Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Radiology, Jiulongpo District People’s Hospital, Chongqing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Haitao Ran, Chongqing Key Laboratory of Ultrasound Molecular Imaging & Department of Ultrasound, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China, Tel +86 13512373563, Email ranhaitao@cqmu.edu.cn Chao Yang, Department of Radiology, Jiulongpo District People’s Hospital, Chongqing, People’s Republic of China, Tel +86 13883095836, Email ychaof737@163.com

Purpose: To address the problem of suboptimal reactive oxygen species (ROS) production in Radiation therapy (RT) which was resulted from exacerbated tumor hypoxia and the heterogeneous distribution of radiation sensitizers.
Materials and Methods: In this work, a novel nanomedicine, designated as PLGA@IR780-Bi-DTPA (PIBD), was engineered by loading the radiation sensitizer Bi-DTPA and the photothermal agent IR780 onto poly(lactic-co-glycolic acid) (PLGA). This design leverages the tumor-targeting ability of IR780 to ensure selective accumulation of the nanoparticles in tumor cells, particularly within the mitochondria. The effect of the photothermal therapy-enhanced radiation therapy was also examined to assess the alleviation of hypoxia and the enhancement of radiation sensitivity.
Results: The PIBD nanoparticles exhibited strong capacity in mitochondrial targeting and selective tumor accumulation. Upon activation by 808 nm laser irradiation, the nanoparticles effectively alleviated local hypoxia by photothermal effect enhanced blood supplying to improve oxygen content, thereby enhancing the ROS production for effective RT. Comparative studies revealed that PIBD-induced RT significantly outperformed conventional RT in treating hypoxic tumors.
Conclusion: This design of tumor-targeting photothermal therapy-enhanced radiation therapy nanomedicine would advance the development of targeted drug delivery system for effective RT regardless of hypoxic microenvironment.

Keywords: Bi-DTPA, IR780, radiotherapy, tumor microenvironment hypoxia, photothermal therapy