Hua Yu, Cao Shichun, Yu Yu, Chu Chengzhen, Yang Ludi, Ge Shengfang, Wang Yefei, You Zhengwei, Yu Jie
State Key Laboratory of Eye Health, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P. R. China.
State Key Laboratory of Advanced Fibers Materials, College of Materials Science and Engineering, Institute of Functional Materials, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai 201620, P. R. China.
ACS Nano. 2025 Jul 22;19(28):26091-26104. doi: 10.1021/acsnano.5c06891. Epub 2025 Jul 10.
Radiation therapy (RT) is a core modality in cancer treatment; however, its efficacy is often limited by tumor resistance. Studies have shown that RT induces abnormal copper ion accumulation and iron reduction, thereby inhibiting ferroptosis and exacerbating therapeutic resistance. In this study, multiomics database analysis revealed that various RT-resistant cancer cell lines and patient-derived tumor models exhibit characteristics of disrupted copper homeostasis and enhanced copper ion-binding capacity. Hence, we have created a pH-responsive nanomicelle system based on dynamic iron-coordinated polyurethane (PCEF@Fe), utilizing a "copper chelation-iron delivery" synergistic strategy to reverse tumor metal metabolism abnormalities. This platform exploits the differential coordination properties of oxime-urethane ligands for copper/ferrous ions, triggering competitive metal exchange in the acidic tumor microenvironment: on one hand, the ligand captures Cu to disrupt copper homeostasis; on the other hand, it releases Fe to promote ferroptosis. Experimental results confirm that PCEF@Fe significantly reduces intracellular copper while increasing iron, enhancing RT sensitivity. Furthermore, fluorescein isothiocyanate was incorporated into PCEF@Fe, leading to fluorescence properties for real-time monitoring of the distribution and metabolic process. In conclusion, this study presents an innovative therapeutic approach that integrates RT, copper chelation, ferroptosis induction, and fluorescence nanotechnology to improve cancer treatment outcomes.
放射治疗（RT）是癌症治疗的核心手段；然而，其疗效常常受到肿瘤耐药性的限制。研究表明，放疗会导致异常的铜离子积累和铁含量降低，从而抑制铁死亡并加剧治疗耐药性。在本研究中，多组学数据库分析显示，各种放疗耐药癌细胞系和患者来源的肿瘤模型呈现出铜稳态破坏和铜离子结合能力增强的特征。因此，我们基于动态铁配位聚氨酯构建了一种pH响应性纳米胶束系统（PCEF@Fe），采用“铜螯合-铁递送”协同策略来逆转肿瘤金属代谢异常。该平台利用肟基聚氨酯配体对铜/亚铁离子的不同配位特性，在酸性肿瘤微环境中引发竞争性金属交换：一方面，配体捕获铜以破坏铜稳态；另一方面，它释放铁以促进铁死亡。实验结果证实，PCEF@Fe能显著降低细胞内铜含量，同时增加铁含量，提高放疗敏感性。此外，将异硫氰酸荧光素掺入PCEF@Fe中，使其具有荧光特性，可实时监测其分布和代谢过程。总之，本研究提出了一种创新的治疗方法，将放疗、铜螯合、铁死亡诱导和荧光纳米技术相结合，以改善癌症治疗效果。
