School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Key Laboratory of Electrical Insulation and Thermal Aging, Shanghai Jiao Tong University, Shanghai 200240, China.
Joint Research Center for Precision Medicine, Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai Fengxian Central Hospital, Shanghai 201499, China.
ACS Appl Mater Interfaces. 2021 Sep 22;13(37):44002-44012. doi: 10.1021/acsami.1c11381. Epub 2021 Sep 8.
Ferroptosis therapy (FT) based on the Fenton reaction of ferrous nanoparticles has been becoming a unique strategy for cancer treatment; however, current ferrous nanoparticles suffer from slower Fenton reaction kinetics, lower ferroptosis efficacy, and long-term toxicity, so it is urgent to construct biocompatible ferrous nanomaterials with highly efficient Fenton reaction activity for cancer FT. Inspired by single-atom catalysis and size-determined tumor penetration, we conceived an innovative strategy for constructing ultrasmall zwitterionic polypeptide-coordinated nanohybrids of PCGA@FeNP with about 6 nm by utilizing thiol/hydroxyl-iron cooperative coordination chemistry. The ultrasmall size, unsaturated ferrous coordination, and intracellular acidic pH could accelerate the Fenton reaction, thus boosting the efficacy of ferroptosis. Moreover, those coordinated nanohybrids exhibited prominent photothermia with 59.5% conversion efficiency, further accelerating the Fenton reaction and inducing a synergistic effect between FT and photothermal therapy (PTT). In vitro and in vivo GPX-4 expression ascertained that PCGA@FeNP indeed induced effective FT and synergistic FT-PTT. Remarkably, in vivo FT-PTT completely ablated 4T1 solid tumors by one treatment, presenting outstanding and synergistic antitumor efficacy via the photothermia-boosted ferroptosis and apoptosis pathways. This work supplies a practicable strategy to fabricate ultrasmall zwitterionic coordination nanohybrids for highly efficient cancer FT and FT-PTT theranostics with potential clinical transitions.
基于亚铁纳米粒子芬顿反应的铁死亡治疗（FT）正在成为癌症治疗的一种独特策略；然而，目前的亚铁纳米粒子存在芬顿反应动力学较慢、铁死亡疗效较低和长期毒性等问题，因此迫切需要构建具有高效芬顿反应活性的生物相容性亚铁纳米材料，用于癌症 FT。受单原子催化和尺寸决定的肿瘤穿透性的启发，我们设想了一种通过利用巯基/羟基-铁协同配位化学构建具有约 6nm 的超小两性离子多肽配位纳米杂化物 PCGA@FeNP 的创新策略。超小尺寸、不饱和亚铁配位和细胞内酸性 pH 可以加速芬顿反应，从而提高铁死亡的疗效。此外，这些配位纳米杂化物表现出明显的光热性能，转换效率为 59.5%，进一步加速芬顿反应并诱导铁死亡和光热治疗（PTT）的协同作用。体外和体内 GPX-4 表达证实，PCGA@FeNP 确实诱导了有效的铁死亡，并产生了铁死亡-PTT 的协同作用。值得注意的是，体内 FT-PTT 通过一次治疗完全消融了 4T1 实体瘤，通过光热增强的铁死亡和细胞凋亡途径表现出出色的协同抗肿瘤疗效。这项工作提供了一种实用的策略，用于构建超小两性离子配位纳米杂化物，用于高效癌症 FT 和具有潜在临床转化的铁死亡-PTT 治疗。
