Multifunctional Bismuth Nanoplatforms Augment Radioactive Iodine Therapy in Anaplastic Thyroid Cancer

Xijie Qu,1,2,* Tong Liu,3,* Yu Wang,2,4 Xinyuan Wei,2,4 Ye Yang,1 Liya Gu,1 Kun Yang,2 Jing Zhang,1 Yan Liu,1 Yiqian Liang,1 Yanzhen Zheng,2,4 Aimin Yang1,2 1Department of Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China; 2School of Future Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China; 3Department of Surgical Intensive Care Unit, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China; 4Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, People’s Republic of China*These authors contributed equally to this workCorrespondence: Aimin Yang, Department of Nuclear Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, Shaanxi, 710061, People’s Republic of China, Email yangaimin@mail.xjtu.edu.cn Yanzhen Zheng, Frontier Institute of Science and Technology, Xi’an Jiaotong University, 99 Yanxiang Road, Xi’an, Shaanxi, 710054, People’s Republic of China, Email zheng.yanzhen@xjtu.edu.cnIntroduction: Radioactive iodine (RAI) therapy is a highly specific targeted treatment for thyroid cancer. However, the intrinsic low energy of 131I limits its efficacy in tumor eradication. Additionally, certain thyroid cancers exhibit a loss of sodium/iodine symporter (NIS) function due to severe dedifferentiation, compromising the therapeutic effectiveness of RAI.Methods: Our work was based on two distinct RAI-sensitizing strategies: (1) the generation of secondary electrons by irradiated metallic nanomaterials to promote hydrolysis and enhance reactive oxygen species (ROS) production, and (2) drug-induced reversal of the dedifferentiated phenotype of tumor cells to restore iodine uptake. Accordingly, we developed a multifunctional nanoplatform, termed Bi@Digoxin, by loading digoxin onto bismuth nanoparticles (BiNPs). The physicochemical properties of Bi@Digoxin were systematically characterized. Furthermore, its therapeutic efficacy was rigorously evaluated through in vitro and in vivo experiments, demonstrating significant treatment outcomes.Results: The experiments demonstrate that Bi@Digoxin enhances the efficacy of RAI in Anaplastic thyroid cancer (ATC) through a triple synergistic mechanism: utilizing nanocarriers for efficient delivery of Digoxin to restore NIS function in tumor cells, reversing RAI resistance in ATC; leveraging the high atomic number property of bismuth (Bi) to enhance radiation energy deposition, promoting ROS bursts and DNA double-strand breaks; and combining near-infrared (NIR) laser-triggered controlled drug release with photothermal ablation to significantly inhibit tumor growth.Conclusion: Bi@Digoxin significantly enhances the therapeutic efficacy of RAI, offering a novel synergistic treatment strategy for ATC that combines biosafety and scalable production, with significant potential for clinical translation.Keywords: radioactive iodine, redifferentiation, radiosensitization, photothermal therapy