Aborig Mohamed, Malik Paul R V, Nambiar Shruti, Chelle Pierre, Darko Johnson, Mutsaers Anthony, Edginton Andrea N, Fleck Andre, Osei Ernest, Wettig Shawn
School of Pharmacy, University of Waterloo, Kitchener, ON N2G 1C5, Canada.
Grand River Regional Cancer Centre, Grand River Hospital, Kitchener, ON N2G 1G3, Canada.
Pharmaceutics. 2019 Apr 12;11(4):179. doi: 10.3390/pharmaceutics11040179.
Gold nanoparticles (AuNPs) are a focus of growing medical research applications due to their unique chemical, electrical and optical properties. Because of uncertain toxicity, "green" synthesis methods are emerging, using plant extracts to improve biological and environmental compatibility. Here we explore the biodistribution of green AuNPs in mice and prepare a physiologically-based pharmacokinetic (PBPK) model to guide interspecies extrapolation. Monodisperse AuNPs were synthesized and capped with epigallocatechin gallate (EGCG) and curcumin. 64 CD-1 mice received the AuNPs by intraperitoneal injection. To assess biodistribution, groups of six mice were sacrificed at 1, 7, 14, 28 and 56 days, and their organs were analyzed for gold content using inductively coupled plasma mass spectrometry (ICP-MS). A physiologically-based pharmacokinetic (PBPK) model was developed to describe the biodistribution data in mice. To assess the potential for interspecies extrapolation, organism-specific parameters in the model were adapted to represent rats, and the rat PBPK model was subsequently evaluated with PK data for citrate-capped AuNPs from literature. The liver and spleen displayed strong uptake, and the PBPK model suggested that extravasation and phagocytosis were key drivers. Organ predictions following interspecies extrapolation were successful for rats receiving citrate-capped AuNPs. This work lays the foundation for the pre-clinical extrapolation of the pharmacokinetics of AuNPs from mice to larger species.
金纳米颗粒（AuNPs）因其独特的化学、电学和光学性质，成为医学研究应用中日益关注的焦点。由于其毒性不确定，“绿色”合成方法正在兴起，即利用植物提取物来提高生物和环境相容性。在此，我们探索了绿色AuNPs在小鼠体内的生物分布，并建立了基于生理的药代动力学（PBPK）模型以指导种间外推。合成了单分散的AuNPs，并用表没食子儿茶素没食子酸酯（EGCG）和姜黄素进行封端。64只CD-1小鼠通过腹腔注射接受AuNPs。为评估生物分布，在第1、7、14、28和56天处死每组6只小鼠，并使用电感耦合等离子体质谱（ICP-MS）分析其器官中的金含量。建立了基于生理的药代动力学（PBPK）模型来描述小鼠体内的生物分布数据。为评估种间外推的潜力，将模型中的物种特异性参数进行调整以代表大鼠，随后用文献中柠檬酸盐封端的AuNPs的PK数据对大鼠PBPK模型进行评估。肝脏和脾脏显示出强烈的摄取，PBPK模型表明血管外渗和吞噬作用是关键驱动因素。种间外推后对接受柠檬酸盐封端的AuNPs的大鼠的器官预测是成功的。这项工作为AuNPs药代动力学从小鼠到更大物种的临床前外推奠定了基础。
