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

Abstract

To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.

Keywords:

• nondegradable
• PBPK
• intravenous administration
• phagocytosis
• rats
• nanorods
• gold
• titanium dioxide
• polyacrylamide
• polyethylene glycol coating

Acknowledgments

We would like to thank Professor Joseph W DePierre for his support with linguistic improvements. The study was financed by the Swedish Research Council for Health, Working Life and Welfare (Forte, grant No 2010-0702), Sweden, the NANoREG project of the European Union Seventh Framework Programme (grant No 310584), and the US Environmental Protection Agency under EPA STAR Program (grant No RD-83486001).

Author contributions

All authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.