Iron Oxide Nanoparticles Induce Autophagosome Accumulation through Multiple Mechanisms: Lysosome Impairment, Mitochondrial Damage, and ER Stress

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• 作者：Xudong Zhang ; Hongqiu Zhang ; Xin Liang ; Jinxie Zhang ; Wei Tao ; Xianbing Zhu ; Danfeng Chang ; Xiaowei Zeng ; Gan Liu ; Lin Mei
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：July 5, 2016
• 年：2016
• 卷：13
• 期：7
• 页码：2578-2587
• 全文大小：735K
• 年卷期：0
• ISSN：1543-8392

文摘

Magnetite (iron oxide, Fe₃O₄) nanoparticles have been widely used for drug delivery and magnetic resonance imaging (MRI). Previous studies have shown that many metal-based nanoparticles including Fe₃O₄ nanoparticles can induce autophagosome accumulation in treated cells. However, the underlying mechanism is still not clear. To investigate the biosafety of Fe₃O₄ and PLGA-coated Fe₃O₄ nanoparticles, some experiments related to the mechanism of autophagy induction by these nanoparticles have been investigated. In this study, the results showed that Fe₃O₄, PLGA-coated Fe₃O₄, and PLGA nanoparticles could be taken up by the cells through cellular endocytosis. Fe₃O₄ nanoparticles extensively impair lysosomes and lead to the accumulation of LC3-positive autophagosomes, while PLGA-coated Fe₃O₄ nanoparticles reduce this destructive effect on lysosomes. Moreover, Fe₃O₄ nanoparticles could also cause mitochondrial damage and ER and Golgi body stresses, which induce autophagy, while PLGA-coated Fe₃O₄ nanoparticles reduce the destructive effect on these organelles. Thus, the Fe₃O₄ nanoparticle-induced autophagosome accumulation may be caused by multiple mechanisms. The autophagosome accumulation induced by Fe₃O₄ was also investigated. The Fe₃O₄, PLGA-coated Fe₃O₄, and PLGA nanoparticle-treated mice were sacrificed to evaluate the toxicity of these nanoparticles on the mice. The data showed that Fe₃O₄ nanoparticle treated mice would lead to the extensive accumulation of autophagosomes in the kidney and spleen in comparison to the PLGA-coated Fe₃O₄ and PLGA nanoparticles. Our data clarifies the mechanism by which Fe₃O₄ induces autophagosome accumulation and the mechanism of its toxicity on cell organelles and mice organs. These findings may have an important impact on the clinical application of Fe₃O₄ based nanoparticles.