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Physiologically Based Pharmacokinetic Model for Composite Nanodevices: Effect of Charge and Size on In Vivo Disposition

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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.

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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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Authors and Affiliations

  1. Dept. of Pharmaceutical Sciences,, University at Buffalo SUNY, Buffalo, New York, 14260, USA

    Donald E. Mager, Vidhi Mody & Chao Xu

  2. Dept. of Pharmacy Practice,, University at Buffalo SUNY, Buffalo, New York, 14260, USA

    Alan Forrest

  3. NanoBiotechnology Center at RPCI, Dept. of Radiation Medicine, Roswell Park Cancer Institute, Buffalo, New York, 14263, USA

    Wojciech G. Lesniak, Shraddha S. Nigavekar, Muhammed T. Kariapper, Mohamed K. Khan & Lajos P. Balogh

  4. Radiation Center, Oregon State University, Corvallis, Oregon, USA

    Leah Minc

  5. Dept. of Radiation Oncology,, British Columbia Cancer Agency (BCCA) Vancouver Centre, 600 West 10th Ave., Vancouver, BC, V5Z4E6, Canada

    Mohamed K. Khan

Authors
  1. Donald E. Mager
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  2. Vidhi Mody
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  3. Chao Xu
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  4. Alan Forrest
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  5. Wojciech G. Lesniak
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  6. Shraddha S. Nigavekar
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  7. Muhammed T. Kariapper
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  8. Leah Minc
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  9. Mohamed K. Khan
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  10. Lajos P. Balogh
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Corresponding author

Correspondence to Mohamed K. Khan.

Electronic Supplementary Material

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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)

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Supplementary Table 1

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Supplementary Table 2

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Mager, D.E., Mody, V., Xu, C. et al. Physiologically Based Pharmacokinetic Model for Composite Nanodevices: Effect of Charge and Size on In Vivo Disposition. Pharm Res 29, 2534–2542 (2012). https://doi.org/10.1007/s11095-012-0784-7

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  • DOI: https://doi.org/10.1007/s11095-012-0784-7

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