State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
College of Materials Science and Engineering, Research Center of Magnetic and Electronic Materials, Zhejiang University of Technology, Hangzhou, 310014, China.
Biomaterials. 2025 Feb;313:122795. doi: 10.1016/j.biomaterials.2024.122795. Epub 2024 Aug 31.
Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with I-aPD-L1. The 150 nm USINAs(I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to I while I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.
铁死亡是一种依赖铁的程序性细胞死亡形式，具有逆转传统癌症治疗耐药性的潜力。铁死亡与化学疗法、光动力疗法和 X 射线疗法相结合，已显示出显著提高的治疗效率。放射性药物治疗（RPT）是一种新兴的方法，通过放射性核素递送实现对病变组织的精确辐射。然而，治疗放射性药物在肿瘤区域的积累和保留不足以及癌症耐药性会影响治疗效果。在这里，通过氟苯硼酸修饰的超小铁纳米颗粒（USINPs）与 I-aPD-L1 之间的亲和力制备了可清除肾脏的 USINPs 和 I-aPD-L1 的纳米组装体。150nm 的 USINAs（I-aPD-L1）纳米组装体在血液循环中稳定，能够有效地靶向肿瘤，并在肿瘤微环境中存在 ATP 的情况下分解。体外和体内实验均证明，USINPs 诱导的铁死亡增强了 I 对肿瘤的放射增敏性，而 I 介导的 RPT 进一步增强了铁死亡。同时，RPT 和铁死亡与 PD-L1 免疫检查点阻断治疗相结合引起的免疫原性细胞死亡表现出强烈的抗肿瘤免疫。本研究为提高铁死亡诱导剂和放射性药物的肿瘤积累提供了一种新方法，深入了解了 RPT 与铁死亡之间的相互作用，并提供了一种有效的 SPECT 引导的铁死亡增强放射免疫治疗方法。
