亚铁配合物诱导肿瘤铁死亡的原位诊疗一体化策略

由Fe2+催化芬顿反应诱导的癌细胞铁死亡是肿瘤治疗的新策略之一。但受细胞抗氧化、代谢和肿瘤微环境等因素影响，以及现有监测手段限制，目前体内铁死亡的诱导过程和调控机制尚不明确。我们近期研究发现，一些亚铁配合物(FeIIL)在诱导铁死亡的过程中，弱顺磁性-低自旋态的Fe2+转变为强顺磁性-高自旋态的Fe3+，显著增加MRI的纵向弛豫效率(r1)，这给体内铁死亡研究带来新的机遇。本项目拟以前期筛选获得的先导诊疗探针FeIIEDTA为基础，分别从体外/内水平深入研究肿瘤铁死亡的原位诊断机理，探明pH、螯合剂和铁死亡诱导剂等因素对FeIIEDTA诊疗作用的影响，揭示关键调控因子(H2O2含量、GSH和GPX4表达水平)与铁死亡效率之间的关系和规律，阐明剂型差异(游离型与靶向递送型FeIIEDTA)对体内诊疗作用的影响。上述研究将为发展新一类肿瘤铁死亡诊疗一体化系统和耐药肿瘤的治疗提供依据。

Ferroptosis of cancer cells induced by Fe2+ catalyzed Fenton reaction is one of the new strategies of anti-tumor therapy. However, due to the treatment responses including cellular antioxidant activities, metabolism and tumor microenvironment, as well as the limited existing monitoring methods, the induction process and regulatory mechanisms of ferroptosis in vivo are not clear. Our recent study found that during the induction of ferroptosis by some ferrous complexes (FeIIL), Fe2+ will switch from a weak paramagnetic low-spin state to a strong paramagnetic high-spin state Fe3+, which significantly increases the longitudinal relaxivity (r1) in MRI, this responsive r1 augmentation effect may offer new opportunities for the in vivo study of ferroptosis. Based on our previous screening assessment, we have obtained the potential leading compound (FeIIEDTA) as the theranostic probe. This project intends to study the in-situ diagnosis mechanism of tumor ferroptosis in vitro and in vivo. we will also explore the impact of pH, chelating agents and ferroptosis inducers on FeIIEDTA mediated ferroptosis; reveal the influence of the key regulatory factors (H2O2, GSH, and GPX4 expression levels) on theranostic efficacy of FeIIEDTA. finally, we will investigate and clarify the FeIIEDTA formulations (free and targeted delivery FeIIEDTA) for in vivo diagnosis and treatment. The research project will provide a basis for the development of a new type of ferroptosis theranostic system and for the treatment of drug-resistant tumors.