International Journal of Nanomedicine (Jan 2024)
A pH-Sensitive Nanoparticle as Reactive Oxygen Species Amplifier to Regulate Tumor Microenvironment and Potentiate Tumor Radiotherapy
Abstract
Xiaomei Jiang,1,* Xiaohong Jiang,2,* Dongjie Wu,1 Wanzhu Xie,3 Xiong Liu,1 Jintao Zheng4 1Department of Dermatology, Liuzhou Traditional Chinese Medicine Hospital, Liuzhou, 545001, People’s Republic of China; 2Department of Pharmacy, Shantou University Medical College, Shantou, 515041, People’s Republic of China; 3Department of Rehabilitation, Liuzhou Worker’s Hospital, Liuzhou, 545001, People’s Republic of China; 4Department of Biotechnology and Food Engineering, Guangdong Technology Israel Institute of Technology, Shantou, 515063, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jintao Zheng, Department of Biotechnology and Food Engineering, Guangdong Technology Israel Institute of Technology, Shantou, 515063, People’s Republic of China, Tel +86 156 2584 9047, Email [email protected]: Radiotherapy is a widely used clinical tool for tumor treatment but can cause systemic toxicity if excessive radiation is administered. Although numerous nanoparticles have been developed as radiosensitizers to reduce the required dose of X-ray irradiation, they often have limitations, such as passive reliance on radiation-induced apoptosis in tumors, and little consider the unique tumor microenvironment that contributes radiotherapy resistance.Methods: In this study, we developed and characterized a novel self-assembled nanoparticle containing dysprosium ion and manganese ion (Dy/Mn-P). We systematically investigated the potential of Dy/Mn-P nanoparticles (NPs) as a reactive oxygen species (ROS) amplifier and radiosensitizer to enhance radiation therapy and modulate the tumor microenvironment at the cellular level. Additionally, we evaluated the effect of Dy/Mn-P on the stimulator of interferon genes (STING), an innate immune signaling pathway.Results: Physicochemical analysis demonstrated the prepared Dy/Mn-P NPs exhibited excellent dispersibility and stability, and degraded rapidly at lower pH values. Furthermore, Dy/Mn-P was internalized by cells and exhibited selective toxicity towards tumor cells compared to normal cells. Our findings also revealed that Dy/Mn-P NPs improved the tumor microenvironment and significantly increased ROS generation under ionizing radiation, resulting in a ~70% increase in ROS levels compared to radiation therapy alone. This enhanced ROS generation inhibited ~92% of cell clone formation and greatly contributed to cytoplasmic DNA exposure. Subsequently, the activation of the STING pathway was observed, leading to the secretion of pro-inflammatory immune factors and maturation of dendritic cells (DCs).Conclusion: Our study demonstrates that Dy/Mn-P NPs can potentiate tumor radiotherapy by improving the tumor microenvironment and increasing endogenous ROS levels within the tumor. Furthermore, Dy/Mn-P can amplify the activation of the STING pathway during radiotherapy, thereby triggering an anti-tumor immune response. This novel approach has the potential to expand the application of radiotherapy in tumor treatment.Keywords: radiotherapy, Dy/Mn-P NPs, ROS, tumor microenvironment, STING pathway
