Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Key Laboratory of Chemical Biology of Hebei Province & College of Chemistry and Environmental Science, Hebei University, Baoding, 071002, PR China.
CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, PR China.
Acta Biomater. 2023 Apr 1;160:281-296. doi: 10.1016/j.actbio.2023.02.015. Epub 2023 Feb 22.
The anti-apoptotic mechanism of breast cancer stem cells (BCSCs) makes it an obstacle to traditional apoptosis as the primary way of death. Ferroptosis is a recently reported mode of programmed cell death caused by the accumulation of iron-dependent lipid peroxidation (LPO) in cells. High dependence on iron makes BCSCs more sensitive to ferroptosis. However, the high level of the Prominin2 protein and high concentration of GSH in BCSCs make BCSCs able to efflux excess iron ions and clear LPO, which limits the therapeutic efficacy of ferroptosis in BCSCs. To overcome this obstacle, we designed a hyaluronic acid (HA)-coated siProminin2-loaded FeOOH nanoparticle (FeOOH/siPROM2@HA) to amplify ferroptosis. The FeOOH/siPROM2@HA is stable under physiologically neutral conditions but generates Fe in an acidic microenvironment; meanwhile, the released siProminin2 inhibits its efflux, and then Fe undergoes a redox reaction with endogenous GSH to produce Fe, which initiates the Fenton reaction-based ferroptosis by LPO elevation. Both in vitro and in vivo studies showed that these pH-sensitive NPs significantly inhibited tumor growth by downregulating glutathione peroxidase 4 (GPX4). Overall, this work demonstrates a "three-pronged" strategy for amplified ferroptotic therapy by simultaneously promoting intracellular iron, inhibiting iron efflux, and depleting GSH, which presents a potential strategy for CSC-targeted cancer therapy. STATEMENT OF SIGNIFICANCE: As the root of recurrence and metastasis, breast cancer stem cells (BCSCs) are resistant to traditional apoptotic death, so it is urgent to explore a new death mode for BCSCs. It has been reported that BCSCs are highly iron-dependent and, therefore, more sensitive to ferroptosis; however, the therapeutic efficacy is greatly limited by the overexpression of Prominin2 in BCSCs, which is correlated with resistance to ferroptosis by exocytosis of iron ions. In this work, we designed a hyaluronic acid-coated siProminin2-loaded FeOOH nano-drug (FeOOH/siPROM2@HA) to accelerate ferroptosis of BCSCs by simultaneously increasing iron ion content, inhibiting iron efflux, and scavenging GSH. This "three-pronged" strategy has significant implications for BCSC-targeted cancer therapy.
乳腺癌干细胞（BCSCs）的抗细胞凋亡机制使其成为传统凋亡作为主要死亡方式的障碍。铁死亡是一种最近报道的程序性细胞死亡模式，由细胞内铁依赖性脂质过氧化（LPO）的积累引起。对铁的高度依赖使 BCSCs 对铁死亡更敏感。然而，BCSCs 中 Prominin2 蛋白水平高和 GSH 浓度高，使 BCSCs 能够排出过量的铁离子并清除 LPO，这限制了铁死亡在 BCSCs 中的治疗效果。为了克服这一障碍，我们设计了一种透明质酸（HA）包裹的载 siProminin2 的 FeOOH 纳米颗粒（FeOOH/siPROM2@HA）来放大铁死亡。在生理中性条件下，FeOOH/siPROM2@HA 稳定，但在酸性微环境中产生 Fe；同时，释放的 siProminin2 抑制其外排，然后 Fe 与内源性 GSH 发生氧化还原反应生成 Fe，引发基于 LPO 升高的芬顿反应铁死亡。体外和体内研究均表明，这些 pH 敏感的纳米颗粒通过下调谷胱甘肽过氧化物酶 4（GPX4）显著抑制肿瘤生长。总的来说，这项工作通过同时促进细胞内铁、抑制铁外排和消耗 GSH，展示了一种增强铁死亡治疗的“三管齐下”策略，为针对 CSC 的癌症治疗提供了一种潜在的策略。
意义声明：作为复发和转移的根源，乳腺癌干细胞（BCSCs）对传统的凋亡死亡有抵抗力，因此迫切需要探索一种新的 BCSC 死亡模式。据报道，BCSCs 对铁高度依赖，因此对铁死亡更敏感；然而，由于 BCSCs 中 Prominin2 的过度表达与铁离子外排相关，从而导致铁死亡的抵抗，这极大地限制了铁死亡的治疗效果。在这项工作中，我们设计了一种透明质酸包覆的载 siProminin2 的 FeOOH 纳米药物（FeOOH/siPROM2@HA），通过同时增加铁离子含量、抑制铁外排和清除 GSH，加速 BCSC 的铁死亡。这种“三管齐下”的策略对针对 BCSC 的癌症治疗具有重要意义。
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