Thermal Hydraulics and Multiphase Flow Laboratory, National Centre for Scientific Research "Demokritos", Athens, Greece.
Research Lab of Advanced, Composite, Nano-Materials and Nanotechnology, Materials Science and Engineering Department, School of Chemical Engineering, National Technical University of Athens, Athens, Greece.
Inhal Toxicol. 2022;34(13-14):361-379. doi: 10.1080/08958378.2022.2115592. Epub 2022 Sep 2.
The increasing exposure to gold nanoparticles (AuNPs), due to their wide range of applications, has led to the need for thorough understanding of their biodistribution, following exposure. The objective of this paper is to develop a PBK model in order to study the clearance, retention and translocation of inhaled gold nanoparticles in rats, providing a basis for the understanding of the absorption, distribution, metabolism and elimination (ADME) mechanisms of AuNPs in various organs. A rat PBK computational model was developed, connected to a detailed respiratory model, including the olfactory, tracheobronchial, and alveolar regions. This model was coupled with a Multiple Path Particle Dosimetry (MPPD) model to appropriately simulate the exposure to AuNPs. Three existing in vivo experimental datasets from scientific literature for the biodistribution of inhaled AuNPs for different AuNP sizes and exposure scenarios were utilized for model calibration and validation. The model was calibrated using two individual datasets for nose only inhaled and intratracheally instilled AuNPs, while an independent dataset for nose only inhaled AuNPs was used as external validation. The overall fitting over the three datasets was proved acceptable as shown by the relevant statistical metrics. The influence of several physiological parameters is also studied via a sensitivity analysis, providing useful insights into the mechanisms of NP pharmacokinetics. The key aspects of the inhaled AuNPs biodistribution are discussed, revealing the key mechanisms for the AuNPs absorption routes, the AuNP uptake by secondary organs and the influence of the AuNP size on the translocation from the lungs to blood circulation. The model results together with the model sensitivity analysis clarified the key mechanisms for the inhaled AuNPs biodistribution to secondary organs. It was observed that nose-only inhaled AuNPs of smaller size can enter the blood circulation through secondary routes, such as absorption through the gastrointestinal (GI) lumen, showing that such translocations should not be underestimated in biodistribution modelling. Finally, the computational framework presented in this study can be used as a basis for a more wide investigation of inhaled nanoparticles biodistribution, including interspecies extrapolation of the resulting PBK model for the inhalation and subsequent biodistribution of AuNPs in humans.
由于金纳米粒子（AuNPs）的广泛应用，其暴露量不断增加，因此需要深入了解其在暴露后的体内分布情况。本文旨在建立一个 PBK 模型，以研究吸入金纳米粒子在大鼠体内的清除、保留和转移情况，为理解 AuNPs 在各器官中的吸收、分布、代谢和消除（ADME）机制提供依据。我们建立了一个大鼠 PBK 计算模型，该模型与一个详细的呼吸模型相连，包括嗅觉、气管支气管和肺泡区域。该模型与多路径粒子剂量学（MPPD）模型相结合，以适当模拟 AuNPs 的暴露情况。我们利用来自科学文献的三个现有的体内实验数据集，用于不同 AuNP 尺寸和暴露场景下吸入 AuNP 的体内分布，对模型进行校准和验证。我们使用两个单独的数据集对仅经鼻吸入和气管内滴注的 AuNPs 进行了模型校准，而另一个仅经鼻吸入 AuNPs 的独立数据集则用于外部验证。通过相关统计指标证明，对这三个数据集的整体拟合是可以接受的。此外，还通过敏感性分析研究了几个生理参数的影响，为纳米颗粒药代动力学的机制提供了有用的见解。讨论了吸入 AuNPs 体内分布的关键方面，揭示了 AuNP 吸收途径、次级器官中 AuNP 的摄取以及 AuNP 尺寸对从肺部向血液循环转移的影响的关键机制。模型结果和模型敏感性分析阐明了次级器官中吸入 AuNPs 体内分布的关键机制。观察到较小尺寸的仅经鼻吸入 AuNPs 可以通过次级途径进入血液循环，例如通过胃肠道（GI）腔吸收，这表明在生物分布建模中不应低估这种转移。最后，本研究提出的计算框架可作为更广泛研究吸入纳米颗粒体内分布的基础，包括将所得 PBK 模型用于人类吸入和随后的 AuNP 体内分布的种间外推。
