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

项目摘要和摘要 金纳米粒子作为药物载体在诊断和治疗方面有很好的应用前景 在实验动物中，但将动物结果转化为临床成功的比例很低。目前，此字段为 面临着“出版物多，药品少”的困境。有多个因素导致了 这。一个重要的因素是缺乏一个稳健的模型来整合现有的实验数据来模拟 不同暴露条件下金纳米粒子的靶器官剂量测定及药代动力学外推 场景。另一个关键因素是目前用于治疗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)被用于纳米颗粒，而纳米颗粒可能不是 合适，因为小分子和纳米粒之间的药代动力学不同。已建成 不同大小纳米金在不同给药途径下的大鼠药代动力学研究 给药(即静脉注射、口服、吸入暴露或气管内滴注) 我们合作者的实验室，并基于我们最近发表的基于生理的药代动力学(PBPK) 单次静脉给药后金纳米颗粒的模型，这里我们提出了一种多途径 全身PBPK建模策略来应对这些挑战。这项提案的目标是确定 小分子的PBPK模型的传统路径对路径外推方法是否 适用于金纳米粒子。我们假设传统的路由到路由外推方法 小分子的PBPK模型可能不适用于金纳米颗粒。有两个具体目标 用来检验这一假设的。目的1：建立金纳米粒子的多路径PBPK模型 通常用于小分子的传统PBPK建模方法。目标2：开发一种多层次的 使用一种专门为纳米金设计的新方法来建立金纳米粒子的路径PBPK模型。这 该项目具有新颖性和重要意义，因为纳米药物动力学的路线外推 以前没有经过严格和定量的测试，这是该领域的一个关键障碍。建议数 研究具有广泛的影响，因为：(1)如果目标实现了，我们的假设是正确的，那么它将建立 进行专门针对纳米颗粒的路径到路径外推的合理方法；(2)如果 结果表明，我们的假设是错误的，那么一个新的健壮的多路径PBPK模型将是最小的 我们的结果将极大地提高我们对路径依赖组织的基本理解 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 (图形用户界面)将与其他研究人员共享，从而通过允许 研究人员不完全精通PBPK模型编码，无法使用模型进行定量模拟 以及推论。我们合作伙伴的大量数据集和我们最近发布的PBPK的可用性 建模框架使该方案具有很高的可行性，非常适合R03方案。

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.