Physiologically Based Pharmacokinetic Modeling of Silica Nanoparticles

项目摘要 二氧化硅纳米颗粒是多功能和生物相容性的无机纳米载体，具有巨大的应用潜力。 药物输送其独特的结构组成和多孔性有利于装载大的治疗药物， 用于位点特异性药物递送的有效载荷。在过去的二十年里，我们的团队表征了二氧化硅纳米颗粒 并获得了啮齿类动物的细胞摄取、药代动力学和毒性数据。然而， 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 二氧化硅纳米颗粒在人体中的药代动力学对于它们的临床转化是必不可少的。生理 基于药代动力学（PBPK）建模是一种成熟的策略， 动物到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， 将其外推至人体，以建立器官蓄积与人体剂量之间的关系。PBPK 模型将化合物特异性数据与生物体的生理学相结合， 毒品PBPK模型是机制性的，并且可以解释PBPK的复杂体内转运机制。 纳米颗粒，如调理作用，单核吞噬细胞系统摄取，淋巴转运，和细胞 内化一旦验证了纳米颗粒PBPK模型在临床前模型中的预测性能， 控制纳米颗粒PK的机制可以很容易地外推到人类， 生理信息。可以使用从动物外推的最终人纳米颗粒PBPK模型 for first-in-human人类predictions预测.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特性。我们的长期目标是成功地翻译 二氧化硅纳米粒子作为药物输送载体应用于人体临床。本提案的目标是翻译 纳米颗粒从啮齿动物分布到人类的机制。建议的具体目标是：1） 开发并验证小鼠和大鼠中各种二氧化硅纳米颗粒的PBPK模型，2）外推啮齿动物 将二氧化硅纳米颗粒的PBPK模型应用于人体，并使用临床数据验证预测。拟议 研究解决了评价剂量与器官之间关系的重大未满足需求 二氧化硅纳米颗粒在人体内的累积。我们的研究项目是创新的，因为我们使用 数学建模和模拟技术，使用从我们的实验室研究中获得的数据， 出版的文献。从本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颗粒与药物和大分子的PBPK模型。的pbpk R01提案的模型将包括较大的动物物种，如狗和兔子。

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.