A general mechanism for intracellular toxicity of metal-containing nanoparticles.
A general mechanism for intracellular toxicity of metal-containing nanoparticles.
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DOI：
10.1039/c4nr01234h
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发表时间：
2014-06-21
期刊：
影响因子：
6.7
通讯作者：
Pompa PP
中科院分区：
文献类型：
--
作者：
Sabella S;Carney RP;Brunetti V;Malvindi MA;Al-Juffali N;Vecchio G;Janes SM;Bakr OM;Cingolani R;Stellacci F;Pompa PP
我们展示了含金属NPs诱导毒性的一般机制，称为“溶酶体增强的特洛伊木马效应”，这为设计更安全的NPs提供了设计规则。纳米颗粒的风险评估是全球学术界、工业界和监管界面临的一个关键挑战。实验证据表明，一系列纳米颗粒在体外和体内都具有显著的毒性。全世界的努力旨在揭示这种毒性的潜在机制。在这里，我们表明，溶酶体细胞室的酸性条件引发的细胞内离子释放-颗粒被大量内化-是与纳米颗粒诱导的细胞内毒性相关的级联事件的原因。我们称这种机制为“溶酶体增强的特洛伊木马效应”，因为在纳米颗粒的情况下，设计用于降解外来物体的保护性细胞机制实际上是它们毒性的原因。为了验证我们的假设，我们比较了类似金颗粒的毒性，其主要区别在于内化途径。我们表明，已知直接通过细胞膜的颗粒在经过修饰后毒性更大，因此大部分被内吞作用内化。此外，通过螯合剂和促溶体剂的实验，我们发现不同含金属NPs（如金属、金属氧化物和半导体NPs）的毒性机制主要与相应毒性离子的释放有关。最后，我们表明不能释放有毒离子的颗粒（如稳定涂层的NPs，或金刚石和二氧化硅NPs）对细胞内环境无害。
We demonstrate a general mechanism for the toxicity induced by metal-containing NPs, named “lysosome-enhanced Trojan horse effect”, which provides design rules to engineer safer NPs. The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment – where particles are abundantly internalized – is responsible for the cascading events associated with nanoparticles-induced intracellular toxicity. We call this mechanism a “lysosome-enhanced Trojan horse effect” since, in the case of nanoparticles, the protective cellular machinery designed to degrade foreign objects is actually responsible for their toxicity. To test our hypothesis, we compare the toxicity of similar gold particles whose main difference is in the internalization pathways. We show that particles known to pass directly through cell membranes become more toxic when modified so as to be mostly internalized by endocytosis. Furthermore, using experiments with chelating and lysosomotropic agents, we found that the toxicity mechanism for different metal containing NPs (such as metallic, metal oxide, and semiconductor NPs) is mainly associated with the release of the corresponding toxic ions. Finally, we show that particles unable to release toxic ions (such as stably coated NPs, or diamond and silica NPs) are not harmful to intracellular environments.
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影响因子：
11.2
作者：
Kukowska-Latallo, JF;Candido, KA;Baker, JR
通讯作者：
Baker, JR
影响因子：
38.3
作者：
Bhabra, Gevdeep;Sood, Aman;Case, Charles Patrick
通讯作者：
Case, Charles Patrick
影响因子：
38.3
作者：
Jiang, Wen;Kim, Betty Y. S.;Chan, Warren C. W.
通讯作者：
Chan, Warren C. W.
影响因子：
3.9
作者：
Biscarini, Fabio;Ong, Quy Khac;Stellacci, Francesco
通讯作者：
Stellacci, Francesco
影响因子：
16.1
作者：
Aggarwal P;Hall JB;McLeland CB;Dobrovolskaia MA;McNeil SE
通讯作者：
McNeil SE