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

基于生理学的药代动力学模型和金纳米粒子给药途径依赖性组织分布的分析

• 批准号: 10450369
• 负责人: Zhoumeng Lin
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450369
• 关键词: Physiologically; based; pharmacokinetic; modeling; analysis

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.

项目摘要和摘要 金纳米颗粒已发现有希望的应用，作为诊断和治疗目的的药物载体 在实验动物中，但是动物结果向临床成功的转化很低。目前，此字段是 面对“这么多出版物但很少有毒品”的困境。有多种因素导致 这。一个重要因素是缺乏可靠的模型，该模型可以集成可用的实验数据以模拟 靶器官剂量测定法和外推金纳米颗粒的药代动力学跨不同的暴露 方案。另一个关键因素是目前用于的传统药代动力学分析方法 小分子（例如，药物和环境化学物质）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，因此适当。建造 在不同尺寸的大鼠大鼠之后，在不同尺寸的金纳米颗粒的广泛药代动力学数据集上 从静脉注射，口腔膨胀，吸入暴露或气管内灌输中给药（即 我们的合作者的实验室，并基于我们最近出版的基于物理的药代动力学（PBPK） 单静脉给药后金纳米颗粒的模型，在这里我们提出了一个多路由 全身PBPK建模策略以应对这些挑战。该提议的目的是确定 用于小分子的PBPK模型的传统路线推断外推方法是否是 适用于金纳米颗粒。我们假设传统的路线推断方法 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 伪造来检验这一假设。 AIM 1：使用使用的多路线PBPK模型用于金纳米颗粒 通常用于小分子的传统PBPK建模方法。目标2：开发一个多 使用新方法特别专为纳米颗粒设计的金纳米颗粒的PBPK模型。这 项目是新颖而重要的，因为纳米粒子药代动力学的外推途径的外推具有 之前没有进行严格和定量测试，并且代表了该领域的关键障碍。提议 研究具有广泛的影响，因为：（1）如果实现目标并且我们的假设是正确的，那么它将确定 用于进行专门针对纳米颗粒的路由外推的理性方法； （2）如果是 结果表明我们的假设是错误的，然后在最小情况下，将是一个新的可靠多路由PBPK模型 建立和我们的结果将大大提高我们对路线依赖性组织的基本理解 金纳米颗粒的分布； （3）建议的PBPK模型将转换为图形用户界面 （GUI）将与其他研究人员共享，从而通过允许 研究人员未完全精通PBPK模型编码，以便能够使用模型进行定量模拟 和外推。我们合作者广泛的数据集的可用性以及我们最近发布的PBPK 建模框架使该建议非常可行，非常适合R03程序。