铁凋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。铁性凋亡与化疗的结合,光动力疗法和X射线疗法已证明治疗效率显着提高。放射性药物治疗(RPT)是一种新兴的方法,其通过放射性核素递送实现对患病组织的精确放射。然而,治疗性放射性药物在肿瘤区域的积累和保留不足以及癌症放射抗性影响治疗效果。这里,通过在USINPs上修饰的氟苯基硼酸与131I-aPD-L1的亲和力,制备了肾脏可清除的超小铁纳米粒子(USINPs)和131I-aPD-L1的纳米组装体。150nmUSINA(131I-aPD-L1)纳米组装体在血液循环中稳定,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诱导的铁凋亡将肿瘤放射敏感性增强至131I,而131I介导的RPT进一步增强了铁凋亡。同时,RPT和铁凋亡联合PD-L1免疫检查点阻断治疗引起的免疫原性细胞死亡表现出强烈的抗肿瘤免疫力。本研究提供了一种新的方法来改善铁凋亡诱导物和放射性药物的肿瘤积累,深入了解RPT和铁性凋亡之间的相互作用以及有效的SPECT引导的铁性凋亡增强的放射免疫治疗。
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 131I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131I-aPD-L1. The 150 nm USINAs(131I-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 131I while 131I-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.