BACKGROUND Understanding the in vivo size-dependent pharmacokinetics and toxicity of nanoparticles is crucial to determine their successful development. Systematic studies on the size-dependent biological effects of nanoparticles not only help to unravel unknown toxicological mechanism but also contribute to the possible biological applications of nanomaterial. METHODS In this study, the biodistribution and the size-dependent biological effects of Fe3O4@SiO2-NH2 nanoparticles (Fe@Si-NPs) in three diameters (10, 20 and 40 nm) were investigated by ICP-AES, serum biochemistry analysis and NMR-based metabolomic analysis after intravenous administration in a rat model. RESULTS Our findings indicated that biodistribution and biological activities of Fe@Si-NPs demonstrated the obvious size-dependent and tissue-specific effects. Spleen and liver are the target tissues of Fe@Si-NPs, and 20 nm of Fe@Si-NPs showed a possible longer blood circulation time. Quantitative biochemical analysis showed that the alterations of lactate dehydrogenase (LDH) and uric acid (UA) were correlated to some extent with the sizes of Fe@Si-NPs. The untargeted metabolomic analyses of tissue metabolomes (kidney, liver, lung, and spleen) indicated that different sizes of Fe@Si-NPs were involved in the different biochemical mechanisms. LDH, formate, uric acid, and GSH related metabolites were suggested as sensitive indicators for the size-dependent toxic effects of Fe@Si-NPs. The findings from serum biochemical analysis and metabolomic analysis corroborate each other. Thus we proposed a toxicity hypothesis that size-dependent NAD depletion may occur in vivo in response to nanoparticle exposure. To our knowledge, this is the first report that links size-dependent biological effects of nanoparticles with in vivo NAD depletion in rats. CONCLUSION The integrated metabolomic approach is an effective tool to understand physiological responses to the size-specific properties of nanoparticles. Our results can provide a direction for the future biological applications of Fe@Si-NPs.

中文翻译：

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核壳结构的Fe3O4 @ SiO2-NH2纳米粒子的尺寸依赖性组织特异性生物学效应。

背景技术了解纳米颗粒的体内尺寸依赖性药代动力学和毒性对于确定其成功开发至关重要。对纳米粒子的尺寸依赖性生物学效应的系统研究不仅有助于阐明未知的毒理学机理，而且有助于纳米材料的可能的生物学应用。方法在本研究中，通过ICP-AES，血清生化分析和ICP-AES研究了Fe3O4 @ SiO2-NH2纳米颗粒（Fe @ Si-NPs）在三种直径（10、20和40 nm）中的生物分布和尺寸依赖性的生物学效应。在大鼠模型中静脉内给药后，基于NMR的代谢组学分析。结果我们的发现表明Fe @ Si-NPs的生物分布和生物活性表现出明显的尺寸依赖性和组织特异性效应。脾脏和肝脏是Fe @ Si-NPs的目标组织，Fe @ Si-NPs的20 nm显示可能更长的血液循环时间。定量生化分析表明，乳酸脱氢酶（LDH）和尿酸（UA）的变化在一定程度上与Fe @ Si-NPs的大小有关。组织代谢组（肾脏，肝脏，肺和脾脏）的非靶向代谢组学分析表明，不同大小的Fe @ Si-NPs参与了不同的生化机制。建议将LDH，甲酸，尿酸和GSH相关代谢物作为Fe @ Si-NPs的大小依赖性毒性作用的敏感指标。血清生化分析和代谢组学分析的结果相互证实。因此，我们提出了一种毒性假说，即体内响应纳米颗粒暴露的大小依赖的NAD消耗可能会发生。据我们所知，这是第一个将纳米颗粒的大小依赖性生物学效应与大鼠体内NAD消耗联系起来的报告。结论集成代谢组学方法是了解纳米粒子对尺寸特定性质的生理反应的有效工具。我们的结果可以为Fe @ Si-NPs的未来生物学应用提供方向。