A physiologically based pharmacokinetic model for polyethylene glycol-coated gold nanoparticles of different sizes in adult mice

Abstract

Nanoparticles (NPs) are widely used in various fields of nanomedicine. A systematic understanding of NP pharmacokinetics is crucial in their design, applications, and risk assessment. In order to integrate available experimental information and to gain insights into NP pharmacokinetics, a membrane-limited physiologically based pharmacokinetic (PBPK) model for polyethylene glycol-coated gold (Au) NPs (PEG-coated AuNPs) was developed in mice. The model described endocytosis of the NPs in the liver, spleen, kidneys, and lungs and was calibrated using data from mice that were intravenously injected with 0.85 mg/kg 13 nm and 100 nm PEG-coated AuNPs. The model adequately predicted multiple external datasets for PEG-coated AuNPs of similar sizes (13–20 nm; 80–100 nm), indicating reliable predictive capability in suitable size ranges. Simulation results suggest that endocytosis of NPs is time and size dependent, i.e. endocytosis of larger NPs occurs immediately and predominately from the blood, whereas smaller NPs can diffuse through the capillary wall and their endocytosis appears mainly from the tissue with a 10-h delay, which may be the primary mechanism responsible for the reported size-dependent pharmacokinetics of NPs. Several physiological parameters (e.g. liver weight fraction of body weight) were identified to have a high influence on selected key dose metrics, indicating the need for additional interspecies comparison and scaling studies and to conduct pharmacokinetic studies of NPs in species that are more closely related to humans in these parameters. This PBPK model provides useful insights into the size, time, and species dependence of NP pharmacokinetics.

• Biodistribution
• endocytosis
• gold nanoparticles
• pharmacokinetics
• PBPK modeling

Declaration of interest

The authors report that they have no conflicts of interest. This study was supported by The Kansas Bioscience Authority funds to the Institute of Computational Comparative Medicine (ICCM) at Kansas State University.

Supplementary material available online

Supplementary Tables S1-S4, and Figure S1-S6.