Physiologically based pharmacokinetic modeling and analysis of administration route-dependent tissue distribution of gold nanoparticles

项目总结和摘要 金纳米粒子作为药物载体在诊断和治疗方面有着广阔的应用前景 在实验室动物中，但将动物结果转化为临床成功率很低。目前，该领域在 面临“出版物多，药品少”的困境。有多种因素促成了 这个一个重要的因素是缺乏一个强大的模型，可以整合现有的实验数据来模拟 不同剂量金纳米粒子靶器官剂量学及外推药代动力学 场景另一个关键因素是，目前用于药物代谢的传统药代动力学分析方法， 小分子（例如，药物和环境化学品）用于纳米颗粒，这可能不是 由于小分子和纳米颗粒之间的药代动力学差异，建造 根据不同途径后大鼠中不同尺寸金纳米颗粒的广泛药代动力学数据集， 管理（即，静脉内注射、经口灌胃、吸入暴露或经皮滴注） 我们的合作者的实验室，并根据我们最近发表的生理药代动力学（PBPK） 金纳米粒子静脉给药后的单一途径的模型，在这里，我们提出了一个多途径 全身PBPK建模策略来应对这些挑战。本提案的目的是确定 小分子PBPK模型的传统途径-途径外推方法是否 适用于金纳米颗粒。我们假设传统的路线到路线外推方法 小分子的PBPK模型可能不适用于金纳米颗粒。两个具体目标是 来检验这个假设目的1：开发金纳米颗粒的多途径PBPK模型， 传统的PBPK建模方法通常用于小分子。目标2：建立一个多层次的 路线PBPK模型的金纳米粒子使用新的方法，特别是设计的纳米粒子。这 该项目是新颖和重要的，因为纳米颗粒药代动力学的途径外推具有 以前没有进行过严格的定量测试，这是该领域的一个关键障碍。拟议 研究具有广泛的影响，因为：（1）如果目标实现，我们的假设是正确的，那么它将建立 一种合理的方法，用于进行专门针对纳米颗粒的路线间外推;（2）如果 结果表明，我们的假设是错误的，那么至少一个新的强大的多途径PBPK模型将 我们的研究结果将大大提高我们对途径依赖性组织的基本理解 金纳米粒子的分布;（3）建议的PBPK模型将转换为图形用户界面 (GUI)这将与其他研究人员分享，从而在该领域产生广泛的影响， 不完全精通PBPK模型编码的研究人员无法使用模型进行定量模拟 和推断。我们合作者的广泛数据集和我们最近发布的PBPK的可用性 建模框架使得该方案具有很高的可行性，非常适合R 03项目。

PROJECT SUMMARY AND ABSTRACT Gold nanoparticles have found promising applications as drug carriers for diagnostic and therapeutic purposes in laboratory animals, but the translation of animal results to clinical success is low. Currently, this field is confronting a dilemma of “so many publications but very few drugs”. There are multiple factors contributing to this. One important factor is a lack of a robust model that can integrate available experimental data to simulate target organ dosimetry and extrapolate pharmacokinetics of gold nanoparticles across different exposure scenarios. Another critical factor is that the traditional pharmacokinetic analysis approaches currently used for small molecules (e.g., drugs and environmental chemicals) are used for nanoparticles, which may not be appropriate because of differences in the pharmacokinetics between small molecules and nanoparticles. Built upon the extensive pharmacokinetic datasets for different sizes of gold nanoparticles in rats after different routes of administration (i.e., intravenous injection, oral gavage, inhalational exposure, or intratracheal instillation) from our collaborator’s laboratory and based on our recently published physiologically based pharmacokinetic (PBPK) model for gold nanoparticles after single route of intravenous administration, here we propose a multi-route whole-body PBPK modeling strategy to address these challenges. The objective of this proposal is to determine whether the traditional route-to-route extrapolation approaches of PBPK models for small molecules are appropriate for gold nanoparticles. We hypothesize that the traditional route-to-route extrapolation approaches of PBPK models for small molecules may not be appropriate for gold nanoparticles. Two Specific Aims were formulated to test this hypothesis. Aim 1: To develop a multi-route PBPK model for gold nanoparticles using traditional PBPK modeling approaches that are typically used for small molecules. Aim 2: To develop a multi- route PBPK model for gold nanoparticles using a new approach particularly designed for nanoparticles. This project is novel and significant because the route-to-route extrapolation of nanoparticle pharmacokinetics has not been rigorously and quantitatively tested before and represents a critical barrier in the field. The proposed research has broad impacts because: (1) if the aims are achieved and our hypothesis is true, then it will establish a rational approach for conducting route-to-route extrapolation that is specifically for nanoparticles; (2) if the results suggest that our hypothesis is false, then at minimal a new robust multi-route PBPK model will be established and our results will greatly improve our fundamental understanding of route-dependent tissue distribution of gold nanoparticles; (3) the proposed PBPK models will be converted to a graphical user interface (GUI) that will be shared with other researchers, thereby making a wide impact in the field by allowing researchers not fully versed in PBPK model coding to be able to use the models to make quantitative simulations and extrapolations. The availability of our collaborator’s extensive datasets and our recently published PBPK modeling framework makes this proposal highly feasible and ideally suitable for the R03 program.