Physiologically Based Pharmacokinetic Modeling of Silica Nanoparticles

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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.