Ferroptosis has been recognized as an iron-based nonapoptotic-regulated cell death process. In the quest of resisting the unyielding vehemence of triple-negative breast cancer (TNBC), herein we have showcased the ferroptosis-inducing heteroleptic [LIr_cRu], [LIr_cIr_h], and [LIr_cRe] complexes, enabling them to selectively target “sialic acid”, an overexpressed cancer cell-surface marker. The open-circuit potential (OCP) measurements in live cancer cells revealed the specific interaction between TNBC and the complexes, whereas control experiments with normal cells did not exhibit such interactions. GSH depletion, GPx4 inhibition, NADH/NADPH oxidation, lipid peroxidation, COX-2 activation, and Nrf2 inactivation were meticulously investigated upon treatment with these complexes to establish a strong basis for ferroptosis. Among all complexes, the complex [LIr_cIr_h] (IC₅₀ = 25 ± 2.17 μM) has been well-documented as a potent ferroptosis inducer, which unveils the sturdy interaction with sialic acid possessing the highest binding constant (K_b = 0.71 × 10⁵ M^–1, ΔG = −279345.8026 kcal/mol) along with the highest serum albumin binding affinity (K_HSA = 0.67 × 10⁶ M^–1) and significant DNA intercalation (K_b = 0.56 × 10⁵ M^–1, K_app = 1.06 × 10⁶ M^–1, and C₅₀ of intercalation is 76.56 μM), displaying the decreased current intensity in differential pulse voltammetry (DPV). Moreover, the complex [LIr_cIr_h] exhibited mitochondrial dysfunction and membrane damage (diminished MMP, ΔΨ_m) through the production of copious reactive oxygen species (ROS) in MDA-MB-231 cells upon considerable accumulation in mitochondria (Pearson’s coefficient = 0.842). The analysis of the field emission scanning electron microscopy (FE-SEM) image has marked the vivid membrane damage induced by the complex [LIr_cIr_h], exhibiting ablaze evidence for the destruction of TNBC cells through ferroptosis.

中文翻译：

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唾液酸靶向 Ru（II）/Ir（III）/Re（I） 复合物用于三阴性乳腺癌铁死亡诱导


铁死亡已被公认为一种基于铁的非凋亡调节细胞死亡过程。为了抵抗三阴性乳腺癌 （TNBC） 的顽强性，我们在这里展示了铁死亡诱导的异位 [LIr_cRu]、[LIr_cIr_h] 和 [LIr_cRe] 复合物，使它们能够选择性地靶向“唾液酸”，一种过表达的癌细胞表面标志物。活癌细胞中的开路电位 （OCP） 测量揭示了 TNBC 与复合物之间的特异性相互作用，而正常细胞的对照实验没有表现出这种相互作用。用这些复合物处理后，仔细研究了 GSH 耗竭、GPx4 抑制、NADH/NADPH 氧化、脂质过氧化、COX-2 活化和 Nrf2 失活，为铁死亡奠定了坚实的基础。在所有复合物中，复合物 [LIr_cIr_h] （IC₅₀ = 25 ± 2.17 μM） 已被充分证明是一种有效的铁死亡诱导剂，它揭示了与具有最高结合常数 （K_b = 0.71 × 10⁵ M^–1， ΔG = −279345.8026 kcal/mol） 以及最高血清白蛋白结合亲和力 （K_HSA = 0.67 × 10 6） 的唾液酸的牢固相互作用^M-1）和显著的 DNA 插层（K_b = 0.56 × 10^{5 M-1，K} _app = 1.06 × 10^{6 M-1}，插层的 C₅₀ 为 76.56 μM），显示差分脉冲伏安法 （DPV） 中的电流强度降低。 此外，复合物 [LIr_cIr_h] 在线粒体中大量积累后，通过在 MDA-MB-231 细胞中产生丰富的活性氧 （ROS） 表现出线粒体功能障碍和膜损伤 （MMP 减少，ΔΨ_m） （皮尔逊系数 = 0.842）。场发射扫描电子显微镜 （FE-SEM） 图像的分析标记了复合物 [LIr_cIr_h] 诱导的生动膜损伤，显示出通过铁死亡破坏 TNBC 细胞的燃烧证据。