Carlander Ulrika, Li Dingsheng, Jolliet Olivier, Emond Claude, Johanson Gunnar
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Int J Nanomedicine. 2016 Feb 11;11:625-40. doi: 10.2147/IJN.S94370. eCollection 2016.
To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.
为评估纳米颗粒（NP）的潜在毒性，有关其摄取和处置（生物动力学）的信息至关重要。工业化学品和药物的经验表明，基于生理学的药代动力学（PBPK）建模可以准确描述和预测生物动力学。迄今为止开发的纳米PBPK模型均涉及单一类型的NP。我们此处的目的是扩展最近针对聚乙二醇化聚丙烯酰胺NP的模型，以便为静脉注射到大鼠体内的不可降解NP开发更通用的PBPK模型。相同的模型和生理参数应用于聚乙二醇化聚丙烯酰胺、未包被的聚丙烯酰胺、金和二氧化钛NP，而NP特异性参数则根据与NP在各种组织中积累的实验时间进程的最佳拟合来选择。尽管这四种NP在生物动力学行为及其物理化学性质方面存在广泛差异，但我们的模型充分描述了它们的生物动力学行为。此外，该模拟表明剂量对生物动力学有深远影响，因为较高剂量下吞噬细胞的饱和成为主要限制步骤。最依赖NP类型的拟合模型参数包括血液：组织渗透系数和吞噬摄取速率常数。由于仅使用了四种在特征（剂量、大小、电荷、形状和表面性质）上存在若干差异的NP，因此无法阐明这些特征与NP依赖性模型参数之间的关系，在此背景下还需要更多实验数据。就此而言，相关PBPK分析的静脉生物分布研究将提供最多的见解。
