Physiologically Based Pharmacokinetic Model for Composite Nanodevices: Effect of Charge and Size on In Vivo Disposition
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To characterize temporal exposure and elimination of 5 gold/dendrimer composite nanodevices (CNDs) (5 nm positive, negative, and neutral, 11 nm negative, 22 nm positive) in mice using a physiologically based mathematical model.
400 ug of CNDs is injected intravenously to mice bearing melanoma cell lines. Gold content is determined from plasma and tissue samples using neutron activation analysis. A physiologically based pharmacokinetic (PBPK) model is developed for 5 nm positive, negative, and neutral and 11 nm negative nanoparticles and extrapolated to 22 nm positive particles. A global sensitivity analysis is performed for estimated model parameters.
Negative and neutral particles exhibited similar distribution profiles. Unique model parameter estimates and distribution profiles explain similarities and differences relative to positive particles. The model also explains mechanisms of elimination by kidney and reticuloendothelial uptake in liver and spleen, which varies with particle size and charge.
Since the PBPK model can capture the diverse temporal profiles of non-targeted nanoparticles, we propose that when specific binding ligands are lacking, size and charge of nanodevices govern most of their in vivo interactions.
Key Wordscomposite nanodevices gold PBPK model reticuloendothelial uptake sensitivity analysis
Acknowledgments and Disclosures
This study was supported in part by NIH (5R01 CA104479), DOD (DAMD17-03-1-0018), and DOE (DE-PS01-00NE22740), and also Eli Lilly and Company pre-doctoral fellowship (to C.X.), and a new investigator grant from the American Association of Pharmaceutical Sciences (to D.E.M).
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