Abstract:
A phenomenological rate equation model is constructed to numerically simulate nanoparticle uptake and subsequent cellular response. Polyamidoamine dendrimers (generations 4-6) are modelled and the temporal evolution of the intracellular cascade of; increased levels of reactive oxygen species, intracellular antioxidant species, caspase activation, mitochondrial membrane potential decay, tumour necrosis factor and interleukin generation is simulated, based on experimental observations. The dose and generation dependence of several of these response factors are seen to well represent experimental observations at a range of time points. The model indicates that variations between responses of different cell-lines, including murine macrophages, human keratinocytes and colon cells, can be simulated and understood in terms of different intracellular antioxidant levels, and, within a given cell-line, varying responses of different cytotoxicity assays can be understood in terms of their sensitivities to different intracellular cascade events. The model serves as a tool to interpolate and visualise the range of dose and temporal dependences and elucidate the mechanisms underlying the in vitro cytotoxic response to nanoparticle exposure and describes the interaction in terms of independent nanoparticle properties and cellular parameters, based on reaction rates. Such an approach could be a valid alternative to that of effective concentrations for classification of nanotoxicity and may lay the foundation for future quantitative structure activity relationships and predictive nanotoxicity models.
摘要:
建立了现象学速率方程模型,以数值模拟纳米颗粒的摄取和随后的细胞反应。聚酰胺胺树枝状聚合物(第4-6代)被建模和细胞内级联的时间演变;增加的活性氧的水平,细胞内抗氧化剂物种,caspase激活,线粒体膜电位衰减,模拟肿瘤坏死因子和白细胞介素的产生,基于实验观察。这些响应因子中的几个的剂量和生成依赖性被认为很好地代表了在一系列时间点的实验观察。该模型表明,不同细胞系的反应之间的差异,包括鼠巨噬细胞,人类角质形成细胞和结肠细胞,可以根据不同的细胞内抗氧化剂水平来模拟和理解,and,在给定的细胞系中,不同细胞毒性测定的不同反应可以根据它们对不同细胞内级联事件的敏感性来理解。该模型可作为一种工具,用于插值和可视化剂量和时间依赖性的范围,并阐明对纳米颗粒暴露的体外细胞毒性反应的机制,并根据独立的纳米颗粒特性和细胞参数描述相互作用。基于反应速率。这种方法可能是有效浓度分类的有效替代方法,可以为将来的定量结构活性关系和预测纳米毒性模型奠定基础。