Pharmaceutical Research

, Volume 29, Issue 9, pp 2534–2542 | Cite as

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. KhanEmail author
  • Lajos P. Balogh
Research Paper



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 Words

composite 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).

Supplementary material

11095_2012_784_Fig3_ESM.jpg (84 kb)
Supplementary Figure

Model qualification using the 22 nm positive particles. Simulations for 22 nm positive CNDs using the proposed PBPK model, with an additional parameter for initial fractional uptake in lung. Simulations were conducted using Berkeley Madonna software and show biased results. (JPEG 84 kb)

11095_2012_784_MOESM1_ESM.tiff (1.4 mb)
High Resolution Image 1 (TIFF 1469 kb)
11095_2012_784_MOESM2_ESM.doc (43 kb)
Supplementary Table 1 (DOC 43 kb)
11095_2012_784_MOESM3_ESM.doc (60 kb)
Supplementary Table 2 (DOC 59 kb)
11095_2012_784_MOESM4_ESM.doc (40 kb)
ESM 1 (DOC 40 kb)


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Copyright information

© Springer Science+Business Media, LLC (outside the USA)  2012

Authors and Affiliations

  • Donald E. Mager
    • 1
  • Vidhi Mody
    • 1
  • Chao Xu
    • 1
  • Alan Forrest
    • 2
  • Wojciech G. Lesniak
    • 3
  • Shraddha S. Nigavekar
    • 3
  • Muhammed T. Kariapper
    • 3
  • Leah Minc
    • 4
  • Mohamed K. Khan
    • 3
    • 5
    Email author
  • Lajos P. Balogh
    • 3
  1. 1.Dept. of Pharmaceutical Sciences,University at Buffalo SUNYBuffaloUSA
  2. 2.Dept. of Pharmacy Practice,University at Buffalo SUNYBuffaloUSA
  3. 3.NanoBiotechnology Center at RPCI, Dept. of Radiation MedicineRoswell Park Cancer InstituteBuffaloUSA
  4. 4.Radiation CenterOregon State UniversityCorvallisUSA
  5. 5.Dept. of Radiation Oncology,British Columbia Cancer Agency (BCCA) Vancouver CentreVancouverCanada

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