Physiologically Based Pharmacokinetic Modeling of Silica Nanoparticles

项目总结 二氧化硅纳米颗粒是一种多功能和生物相容的无机纳米载体，具有巨大的应用潜力 药物递送。其独特的结构组成和孔隙率便于装载大剂量的治疗性药物 现场特定药物输送的有效载荷。在过去的二十年里，我们的团队表征了二氧化硅纳米颗粒 并获得了啮齿动物细胞摄取、药代动力学和毒性的数据。然而，人们对此知之甚少。 关于二氧化硅纳米颗粒在人体内的药代动力学和生物分布。更好地理解 二氧化硅纳米粒在人体内的药代动力学对其临床翻译是必不可少的。生理上 基于药代动力学(PBPK)的建模是一种成熟的策略，可以将机械学知识从 从动物到人类。我们建议在小鼠和大鼠体内建立二氧化硅纳米颗粒的PBPK模型 将它们外推到人类身上，以建立器官积累和人类剂量之间的关系。PBPK 模型将化合物的特定数据与生物体的生理学相结合，以预测药物动力学 毒品。PBPK模型是机械性的，可以解释复杂的体内转运机制 纳米粒子，如调理作用、单核巨噬细胞系统摄取、淋巴转运和细胞 内部化。一旦验证了临床前模型中纳米粒子PBPK模型的预测性能， 控制纳米粒子PK的机制可以很容易地外推到人类身上，通过替换相关的 生理信息。从动物外推的最终的人类纳米粒子PBPK模型可以使用 这是人类第一次做出预测。目前还没有可用于二氧化硅纳米颗粒的PBPK模型 外推到人类所需的所有相关性质。我们的长期目标是成功地翻译 二氧化硅纳米颗粒作为药物输送载体应用于人体临床。这项提议的目标是将 纳米颗粒从啮齿动物到人类的分布机制。该提案的具体目的是：1) 在小鼠和大鼠体内建立和验证各种二氧化硅纳米颗粒的PBPK模型，2)推断啮齿动物 将二氧化硅纳米粒子的PBPK模型应用于人类，并使用临床数据验证预测。建议数 研究解决了评估剂量和器官之间关系的一个重要的未得到满足的需求 二氧化硅纳米颗粒在人体内的积累。我们的研究项目具有创新性，因为我们使用了 数学建模和模拟技术，使用从我们的实验室研究和 出版的文学作品。从这项研究项目中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提案的模型将包括狗和兔子等较大的动物物种。

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.