Systematic Investigation of the Physicochemical Factors That Contribute to the Toxicity of ZnO Nanoparticles

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• 作者：Qingshan Mu ; Calin A. David ; Josep Galceran ; Carlos Rey-Castro ; 艁ukasz Krzemi艅ski ; Rachel Wallace ; Faith Bamiduro ; Steven J. Milne ; Nicole S. Hondow ; Rik Brydson ; Gema Vizcay-Barrena ; Michael N. Routledge ; Lars J. C. Jeuken ; Andy P. Brown
• 刊名：Chemical Research in Toxicology
• 出版年：2014
• 出版时间：April 21, 2014
• 年：2014
• 卷：27
• 期：4
• 页码：558-567
• 全文大小：630K
• 年卷期：v.27,no.4(April 21, 2014)
• ISSN：1520-5010

文摘

ZnO nanoparticles (NPs) are prone to dissolution, and uncertainty remains whether biological/cellular responses to ZnO NPs are solely due to the release of Zn²⁺ or whether the NPs themselves have additional toxic effects. We address this by establishing ZnO NP solubility in dispersion media (Dulbecco鈥檚 modified Eagle鈥檚 medium, DMEM) held under conditions identical to those employed for cell culture (37 掳C, 5% CO₂, and pH 7.68) and by systematic comparison of cell鈥揘P interaction for three different ZnO NP preparations. For NPs at concentrations up to 5.5 渭g ZnO/mL, dissolution is complete (with the majority of the soluble zinc complexed to dissolved ligands in the medium), taking ca. 1 h for uncoated and ca. 6 h for polymer coated ones. Above 5.5 渭g/mL, the results are consistent with the formation of zinc carbonate, keeping the solubilized zinc fixed to 67 渭M of which only 0.45 渭M is as free Zn²⁺, i.e., not complexed to dissolved ligands. At these relatively high concentrations, NPs with an aliphatic polyether-coating show slower dissolution (i.e., slower free Zn²⁺ release) and reprecipitation kinetics compared to those of uncoated NPs, requiring more than 48 h to reach thermodynamic equilibrium. Cytotoxicity (MTT) and DNA damage (Comet) assay dose鈥搑esponse curves for three epithelial cell lines suggest that dissolution and reprecipitation dominate for uncoated ZnO NPs. Transmission electron microscopy combined with the monitoring of intracellular Zn²⁺ concentrations and ZnO鈥揘P interactions with model lipid membranes indicate that an aliphatic polyether coat on ZnO NPs increases cellular uptake, enhancing toxicity by enabling intracellular dissolution and release of Zn²⁺. Similarly, we demonstrate that needle-like NP morphologies enhance toxicity by apparently frustrating cellular uptake. To limit toxicity, ZnO NPs with nonacicular morphologies and coatings that only weakly interact with cellular membranes are recommended.