Biodegradable copper-iodide clusters modulate mitochondrial function and suppress tumor growth under ultralow-dose X-ray irradiation

• Published in: Nature communications 2024-09, Vol.15 (1), p.8092-13
• Main Authors: Ma, Xiaoqian, Lin, Nuo, Yang, Qing, Liu, Peifei, Ding, Haizhen, Xu, Mengjiao, Ren, Fangfang, Shen, Zhiyang, Hu, Ke, Meng, Shanshan, Chen, Hongmin
• Format: Article
• Language: English
• Subjects: 639/925/352/2733; 692/4028/67/1059/485; 692/700/565/485; Animals; Antitumor activity; Bcl-2 protein; Biodegradability; Biodegradation; Bovine serum albumin; Cancer therapies; Cell death; Cell Line, Tumor; Chelation; Clusters; Copper; Copper - chemistry; DNA damage; Female; Functional groups; Humanities and Social Sciences; Humans; In vivo methods and tests; Iodides; Iodides - chemistry; Iodides - metabolism; Iodine; Ions; Irradiation; Mice; Mice, Inbred BALB C; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - radiation effects; Mitochondrial DNA; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - radiotherapy; Oxidative stress; Phosphors; Photosensitizing Agents - pharmacology; Radiation damage; Radiation dosage; Radiation effects; Radiosensitization; Science; Science (multidisciplinary); Serum albumin; Serum Albumin, Bovine - chemistry; Serum Albumin, Bovine - metabolism; Singlet oxygen; Tricarboxylic acid cycle; Tumor cells; Tumors; X ray irradiation; X-Rays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52278-6

Both copper (Cu 2+/+ ) and iodine (I − ) are essential elements in all living organisms. Increasing the intracellular concentrations of Cu or I ions may efficiently inhibit tumor growth. However, efficient delivery of Cu and I ions into tumor cells is still a challenge, as Cu chelation and iodide salts are highly water-soluble and can release in untargeted tissue. Here we report mitochondria-targeted Cu-I cluster nanoparticles using the reaction of Cu + and I − to form stable bovine serum albumin (BSA) radiation-induced phosphors (Cu-I@BSA). These solve the stability issues of Cu + and I − ions. Cu-I@BSA exhibit bright radioluminescence, and easily conjugate with the emission-matched photosensitizer and targeting molecule using functional groups on the surface of BSA. Investigations in vitro and in vivo demonstrate that radioluminescence under low-dose X-ray irradiation excites the conjugated photosensitizer to generate singlet oxygen, and combines with the radiosensitization mechanism of the heavy atom of iodine, resulting in efficient tumor inhibition in female mice. Furthermore, our study reveals that BSA protection causes the biodegradable Cu-I clusters to release free Cu and I ions and induce cell death by modulating mitochondrial function, damaging DNA, disrupting the tricarboxylic acid cycle, decreasing ATP generation, amplifying oxidative stress, and boosting the Bcl-2 pathway. Efficient delivery of copper and iodine ions into tumor cells is promising for boosting the antitumor effect but elusive. Here the authors report a mitochondrial-targeted copper-iodide nanoparticles for the cancer treatment in which copper and iodide ions induce cell death by modulating mitochondrial functions under low-dose Xray irradiation.