Physiologically based pharmacokinetic model for composite nanodevices: Effect of charge and size on in vivo disposition

Donald E. Mager, Vidhi Mody, Chao Xu, Alan Forrest, Wojciech G. Lesniak, Shraddha S. Nigavekar, Muhammed T. Kariapper, Leah Minc, Mohamed K. Khan, Lajos P. Balogh

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose 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. Methods 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. Results 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)2534-2542
Number of pages9
JournalPharmaceutical Research
Volume29
Issue number9
DOIs
StatePublished - Sep 2012
Externally publishedYes

Keywords

  • Composite nanodevices
  • Gold
  • PBPK model
  • Reticuloendothelial uptake
  • Sensitivity analysis

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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