Physiologically Based Pharmacokinetic Modeling of Silica Nanoparticles

基于生理学的二氧化硅纳米颗粒药代动力学模型

基本信息

批准号：
10508729
负责人：
Venkata K Yellepeddi
金额：
$ 8.11万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-06 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10508729
关键词：
Address Animal Model Animals Biodistribution Canis familiaris Characteristics Clinical Clinical Data Clinical Pharmacology Complex Data Development Dose Drug Delivery Systems Drug Kinetics Drug Modelings Goals Human Infrastructure Knowledge Laboratory Study Literature Mathematical Model Simulation Mathematics Medical Modeling Mononuclear Mus Organ Organism Oryctolagus cuniculus Performance Phagocytes Pharmaceutical Preparations Physiological Physiology Porosity Pre-Clinical Model Principal Investigator Property Publishing Rattus Recording of previous events Research Research Project Grants Rodent Rodent Model Shapes Silicon Dioxide Site Surface System Techniques Therapeutic Toxic effect Translating Utah biomaterial compatibility clinical translation delivery vehicle experience first-in-human in vivo innovation lymphatic circulation macromolecule nanocarrier nanoparticle nanoparticle drug pharmacokinetic model physiologically based pharmacokinetics pre-clinical predictive modeling tool uptake

项目摘要

PROJECT SUMMARY Silica nanoparticles are multifunctional and biocompatible inorganic nanocarriers with enormous potential for drug delivery. Their unique structural composition and porosity facilitates the loading of large therapeutic payloads for site-specific drug delivery. Since past two decades our team characterized silica nanoparticles and obtained data on cellular uptake, pharmacokinetics, and toxicity in rodents. However, very little is known about pharmacokinetics and biodistribution of silica nanoparticles in humans. A better understanding of the pharmacokinetics of silica nanoparticles in humans is essential for their clinical translation. Physiologically based pharmacokinetic (PBPK) modeling is well established strategy to translate mechanistic knowledge from animals to humans. We propose to develop PBPK models of silica nanoparticles in mice and rats and extrapolate them to humans to establish a relationship between organ accumulation, and human dose. PBPK models integrate compound specific data with physiology of the organism to predict the pharmacokinetics of drugs. PBPK models are mechanistic and can account for complex in vivo transport mechanisms of nanoparticles such as opsonization, mononuclear phagocyte system uptake, lymphatic transport, and cellular internalization. Once the predictive performance of nanoparticle PBPK models in preclinical models is verified, the mechanisms governing nanoparticle PK can be easily extrapolated to humans by replacing relevant physiological information. The final human nanoparticle PBPK model extrapolated from animals can be used for first-in-human predictions. There are no PBPK models available for silica nanoparticles that can incorporate all relevant properties required for extrapolation to humans. Our long-term goal is to successfully translate silica nanoparticles to human clinical use as drug delivery vehicles. The objective of this proposal is to translate the mechanisms of nanoparticle distribution from rodents to humans. The Specific Aims of the proposal are: 1) Develop and validate PBPK models for various silica nanoparticles in mice and rats, 2) Extrapolate the rodent PBPK model of silica nanoparticles to humans and verify the predictions using clinical data. The proposed research addresses a significant unmet need for evaluating the relationship between dose and organ accumulation of silica nanoparticles in humans. Our research project is innovative because we use mathematical modeling and simulation techniques that use data obtained from our laboratory studies and published literature. The data obtained from this research project will be used for submitting an R01 application to develop and validate PBPK models for silica nanoparticles with drugs and macromolecules. The PBPK models for the R01 proposal will include larger animal species such as dogs and rabbits.

项目概要二氧化硅纳米粒子是多功能和生物相容性无机纳米载体，具有巨大的应用潜力药物输送。其独特的结构组成和孔隙率有利于装载大量治疗药物用于特定位点药物输送的有效负载。过去二十年以来，我们的团队对二氧化硅纳米粒子进行了表征并获得了啮齿类动物的细胞摄取、药代动力学和毒性数据。然而，人们知之甚少关于二氧化硅纳米粒子在人体中的药代动力学和生物分布。更好地理解二氧化硅纳米粒子在人体中的药代动力学对其临床转化至关重要。生理上基于药代动力学 (PBPK) 模型是一种成熟的策略，可将机械知识转化为动物对人类。我们建议在小鼠和大鼠中开发二氧化硅纳米颗粒的 PBPK 模型将它们外推到人体，以建立器官积累与人体剂量之间的关系。 PBPK 模型将化合物特定数据与生物体生理学相结合，以预测药物的药代动力学药物。 PBPK 模型是机械性的，可以解释复杂的体内转运机制纳米颗粒，例如调理作用、单核吞噬细胞系统摄取、淋巴转运和细胞内化。一旦纳米颗粒 PBPK 模型在临床前模型中的预测性能得到验证，通过替换相关的纳米粒子 PK 的机制可以很容易地推断到人类生理信息。可以使用从动物推断的最终人类纳米颗粒 PBPK 模型进行首次人类预测。没有可用于二氧化硅纳米颗粒的 PBPK 模型可以结合外推到人类所需的所有相关属性。我们的长期目标是成功翻译二氧化硅纳米颗粒在人类临床上用作药物输送载体。该提案的目标是翻译纳米粒子从啮齿动物到人类的分布机制。该提案的具体目标是：1) 开发并验证小鼠和大鼠体内各种二氧化硅纳米粒子的 PBPK 模型，2) 推断啮齿动物二氧化硅纳米颗粒对人体的 PBPK 模型，并使用临床数据验证预测。拟议的研究解决了评估剂量与器官之间关系的重大未满足需求二氧化硅纳米粒子在人体中的积累。我们的研究项目具有创新性，因为我们使用使用从我们实验室研究获得的数据的数学建模和模拟技术出版的文献。从该研究项目获得的数据将用于提交 R01 申请开发和验证二氧化硅纳米粒子与药物和大分子的 PBPK 模型。 PBPK R01 提案的模型将包括较大的动物物种，例如狗和兔子。