When suspended in cell culture medium, nano-objects composed of soluble metals such as silver can dissolve resulting in ion formation, altered particle properties (e.g. mass, morphology, etc.), and modulated cellular dose. Cultured cells are exposed not just to nanoparticles but to a complex, dynamic mixture of altered nanoparticles, unbound ions, and ion-ligand complexes. Here, three different cell types (RAW 264.7 macrophages and bone marrow derived macrophages from wild-type C57BL/6 J mice and Scavenger Receptor A deficient (SR-A(−/−)) mice) were exposed to 20 and 110 nm silver nanoparticles, and RAW 264.7 cells were exposed to freshly mixed silver ions, aged silver ions (ions incubated in cell culture medium), and ions formed from nanoparticle dissolution. The In Vitro Sedimentation, Diffusion, Dissolution, and Dosimetry Model (ISD3) was used to predict dose metrics for each exposure scenario. Silver nanoparticles, freshly mixed ions, and ions from nanoparticle dissolution were toxic, while aged ions were not toxic. Macrophages from SR-A(−/−) mice did not take up 20 nm silver nanoparticles as well as wild-types but demonstrated no differences in silver levels after exposure to 110 nm nanoparticles. Dose response modeling with ISD3 predicted dose metrics suggest that amount of ions in cells and area under the curve (AUC) of ion amount in cells are the most predictive of cell viability after nanoparticle and combined nanoparticle/dissolution-formed-ions exposures, respectively. Results of this study suggest that the unbound silver cation is the ultimate toxicant, and ions formed extracellularly drive toxicity after exposure to nanoparticles. Applying computational modeling (ISD3) to better understand dose metrics for soluble nanoparticles allows for better interpretation of in vitro hazard assessments.

中文翻译：

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所有的银都没有毒性：银离子和粒子动力学揭示了银离子老化和剂量测定对银纳米粒子毒性的作用

当悬浮在细胞培养基中时，由可溶性金属（例如银）组成的纳米物体可以溶解，导致离子形成、改变颗粒特性（例如质量、形态等）并调节细胞剂量。培养的细胞不仅暴露于纳米颗粒，而且暴露于改变的纳米颗粒、未结合离子和离子-配体复合物的复杂动态混合物。在这里，三种不同的细胞类型（RAW 264.7 巨噬细胞和来自野生型 C57BL/6 J 小鼠和清道夫受体 A 缺陷 (SR-A(−/−)) 小鼠的骨髓来源的巨噬细胞）暴露于 20 和 110 nm 银纳米粒子和 RAW 264.7 细胞暴露于新鲜混合的银离子、老化的银离子（在细胞培养基中孵育的离子）和纳米颗粒溶解形成的离子。体外沉降、扩散、溶解和剂量测定模型 (ISD3) 用于预测每种暴露场景的剂量指标。银纳米颗粒、新混合的离子和纳米颗粒溶解的离子是有毒的，而老化的离子则无毒。SR-A(−/−) 小鼠的巨噬细胞不像野生型小鼠那样吸收 20 nm 银纳米颗粒，但在暴露于 110 nm 纳米颗粒后银水平没有差异。使用 ISD3 预测剂量指标的剂量响应建模表明，细胞中的离子量和细胞中离子量的曲线下面积 (AUC) 分别最能预测纳米颗粒和纳米颗粒/溶解形成离子组合暴露后的细胞活力。这项研究的结果表明，未结合的银阳离子是最终的毒物，接触纳米颗粒后，细胞外形成的离子会产生毒性。应用计算模型 (ISD3) 更好地了解可溶性纳米粒子的剂量指标，可以更好地解释体外危险评估。