Iron oxide nanoparticles (IONs) are frequently used in various biomedical applications, in particular as magnetic resonance imaging contrast agents in liver imaging. Indeed, number of IONs have been withdrawn due to their poor clinical performance. Yet comprehensive understanding of their interactions with hepatocytes remains relatively limited. Here we investigated how iron oxide nanocubes (IO-cubes) and clusters of nanocubes (IO-clusters) affect distinct human hepatic cell lines. The viability of HepG2, Huh7 and Alexander cells was concentration-dependently decreased after exposure to either IO-cubes or IO-clusters. We found similar cytotoxicity levels in three cell lines triggered by both nanoparticle formulations. Our data indicate that different expression levels of Bcl-2 predispose cell death signaling mediated by nanoparticles. Both nanoparticles induced rather apoptosis than autophagy in HepG2. Contrary, IO-cubes and IO-clusters trigger distinct cell death signaling events in Alexander and Huh7 cells. Our data clarifies the mechanism by which cubic nanoparticles induce autophagic flux and the mechanism of subsequent toxicity. These findings imply that the cytotoxicity of ION-based contrast agents should be carefully considered, particularly in patients with liver diseases.

中文翻译：

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氧化铁纳米颗粒诱导的渐进性溶酶体膜透化可驱动肝细胞自噬和凋亡。

氧化铁纳米粒子（ION）经常用于各种生物医学应用，特别是在肝脏成像中用作磁共振成像造影剂。事实上，许多 ION 已因临床表现不佳而被撤回。然而，对其与肝细胞相互作用的全面了解仍然相对有限。在这里，我们研究了氧化铁纳米立方体（IO-立方体）和纳米立方体簇（IO-簇）如何影响不同的人类肝细胞系。HepG2、Huh7 和 Alexander 细胞的活力在暴露于 IO 立方体或 IO 簇后呈浓度依赖性下降。我们发现两种纳米颗粒制剂在三种细胞系中触发的细胞毒性水平相似。我们的数据表明，Bcl-2 的不同表达水平易导致纳米粒子介导的细胞死亡信号传导。两种纳米粒子在 HepG2 中诱导的不是细胞凋亡，而是自噬。相反，IO 立方体和 IO 簇在 Alexander 和 Huh7 细胞中触发不同的细胞死亡信号事件。我们的数据阐明了立方纳米粒子诱导自噬流的机制以及随后的毒性机制。这些发现意味着应仔细考虑基于 ION 的造影剂的细胞毒性，特别是对于患有肝病的患者。