Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles

Area of Science:

• Nanotoxicology and Pharmacokinetics
• Biomedical Engineering
• Materials Science

Background:

• Assessing nanoparticle (NP) toxicity requires understanding their uptake and disposition (biokinetics).
• Physiologically-based pharmacokinetic (PBPK) modeling accurately predicts chemical and drug biokinetics.
• Existing nano-PBPK models are limited to single NP types.

Purpose of the Study:

• To develop a generalized PBPK model for non-degradable NPs injected intravenously into rats.
• To extend a previous model for pegylated polyacrylamide NPs.
• To apply the model to various NP types, including pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs.

Main Methods:

• Applied a single PBPK model structure and physiological parameters to four different NP types.
• Adjusted NP-specific parameters to best fit experimental NP accumulation data in rat tissues.
• Investigated the impact of dose on NP biokinetics through simulation.

Main Results:

• The generalized PBPK model adequately described the biokinetic behavior of all four NP types, despite differing properties.
• Simulations showed that high doses saturate phagocytic cells, significantly limiting NP uptake and altering disposition.
• Key NP-dependent parameters included blood:tissue permeability coefficients and phagocytic uptake rates.

Conclusions:

• A generalized PBPK model can effectively describe the biokinetics of various non-degradable NPs.
• Dose-dependent saturation of phagocytic clearance is a critical factor in NP biokinetics.
• Further experimental biodistribution studies and PBPK analyses are needed to elucidate NP characteristic-dependent parameters.