BACKGROUND The physiologically based pharmacokinetic (PBPK) model is a useful tool to predict the pharmacokinetics of various types of nanoparticles (NPs). The endocytosis mechanism plays a key role in pharmacokinetics of NPs. However, the effect of endocytosis mechanism both in the blood and tissue are seldom considered in PBPK model. OBJECTIVES To investigate the biodistribution of intravenously injected pegylated AuNPs in mice and human using PBPK model considering the endocytosis mechanism both in the blood and tissue. METHODS Taking polyethylene glycol-coated gold nanoparticles (AuNPs) as an example, we developed a PBPK model to explore biodistribution of different size AuNPs. In the model, we considered the role of endocytosis mechanism both in the blood and tissue. In addition, the size-dependent permeability coefficient, excretion rate constant, phagocytic capacity, uptake rate, and release rate were derived from literatures. The mice PBPK model was extrapolated to the human by changing physiology parameters and the number of phagocytic cell (PCs). RESULTS AuNPs were primarily distributed in the blood, liver, and spleen regardless of particle size, and almost all captured by the PCs in the liver and spleen, while few was captured in the blood. There are more organ distribution and longer circulation for smaller NPs. The 24-h accumulation of AuNPs decreased with increasing size in the most organ, while the accumulation of AuNPs showed an inverted U-shaped curve in the liver and slight U-shaped curve in the blood. The human results of model-predicted displayed a similar tendency with those in mice. Size, partition coefficients, and body weight were the key factors influencing the organ distribution of AuNPs. CONCLUSIONS The size played an important role on the distribution and accumulation of AuNPs in various tissues. Our PBPK model was well predicted the NPs distribution in mice and human. A better understanding of these mechanisms could provide effective guides for nanomedine delivery.

中文翻译：

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纳米颗粒的基于生理的药代动力学建模中的胞吞机制。

背景技术基于生理学的药代动力学（PBPK）模型是预测各种类型的纳米颗粒（NP）的药代动力学的有用工具。内吞作用机制在NPs的药代动力学中起关键作用。然而，在PBPK模型中很少考虑血液和组织中内吞作用机制的作用。目的利用PBPK模型研究小鼠和人静脉注射的聚乙二醇化AuNPs在血液和组织中的内吞作用机理，探讨其在小鼠和人体内的生物分布。方法以聚乙二醇包覆的金纳米颗粒（AuNPs）为例，我们开发了一个PBPK模型来研究不同大小的AuNPs的生物分布。在模型中，我们考虑了内吞机制在血液和组织中的作用。此外，尺寸相关的渗透系数 排泄率常数，吞噬能力，​​摄取率和释放率均来自文献。通过改变生理参数和吞噬细胞（PCs）的数量，将小鼠PBPK模型外推到人类。结果AuNPs主要分布在血液，肝脏和脾脏中，而与颗粒大小无关，几乎所有PCs都将其捕获在肝脏和脾脏中，而很少捕获到血液中。对于较小的NP，器官分布更多，循环时间更长。在大多数器官中，AuNPs的24小时积累随着大小的增加而减少，而AuNPs的积累在肝脏中显示为倒U形曲线，而在血液中则显示为微U形曲线。模型预测的人类结果显示出与小鼠相似的趋势。大小，分配系数，体重是影响AuNPs器官分布的关键因素。结论大小在各种组织中AuNPs的分布和积累中起着重要作用。我们的PBPK模型可以很好地预测小鼠和人类中NP的分布。对这些机制的更好理解可以为纳米药物的输送提供有效的指导。