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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

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.

Key Words

composite nanodevices gold PBPK model reticuloendothelial uptake sensitivity analysis 

Notes

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)

References

  1. 1.
    Gabizon A, Papahadjopoulos D. Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci. 1988;85(18):6949–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Lesniak W, Bielinska AU, Sun K, Janczak KW, Shi X, Baker JR, et al. Silver/dendrimer nanocomposites as biomarkers: fabrication, characterization, in vitro toxicity, and intracellular detection. Nano Letters. 2005;5(11):2123–30.PubMedCrossRefGoogle Scholar
  3. 3.
    Khan MK, Minc LD, Nigavekar SS, Kariapper MST, Nair BM, Schipper M, et al. Fabrication of 198Au0 radioactive composite nanodevices and their use for nanobrachytherapy. Nanomed Nanotechnol Biol Med. 2008;4(1):57–69.CrossRefGoogle Scholar
  4. 4.
    Shi X, Wang S, Meshinchi S, Van Antwerp ME, Bi X, Lee I, et al. Dendrimer-entrapped gold nanoparticles as a platform for cancer-cell targeting and imaging. Small. 2007;3(7):1245–52.PubMedCrossRefGoogle Scholar
  5. 5.
    Crooks RM, Zhao M, Sun L, Chechik V, Yeung LK. Dendrimer-encapsulated metal nanoparticles: synthesis, characterization, and applications to catalysis. Acc Chem Res. 2000;34(3):181–90.CrossRefGoogle Scholar
  6. 6.
    Menjoge AR, Kannan RM, Tomalia DA. Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications. Drug Discov Today. 2010;15(5–6):171–85.PubMedCrossRefGoogle Scholar
  7. 7.
    Lee CC, MacKay JA, Frechet JMJ, Szoka FC. Designing dendrimers for biological applications. Nat Biotech. 2005;23(12):1517–26. doi: 10.1038/nbt1171.CrossRefGoogle Scholar
  8. 8.
    Balogh L, Nigavekar SS, Nair BM, Lesniak W, Zhang C, Sung LY, et al. Significant effect of size on the in vivo biodistribution of gold composite nanodevices in mouse tumor models. Nanomed Nanotechnol Biol Med. 2007;3(4):281–96.CrossRefGoogle Scholar
  9. 9.
    Khan MK, Nigavekar SS, Minc LD, Kariapper MS, Nair BM, Lesniak WG, et al. In vivo biodistribution of dendrimers and dendrimer nanocomposites—implications for cancer imaging and therapy. Technol Cancer Res Treat. 2005;4(6):603–13.PubMedGoogle Scholar
  10. 10.
    Mager DE. Quantitative structure-pharmacokinetic/pharmacodynamic relationships. Adv Drug Deliv Rev. 2006;58(12–13):1326–56.PubMedCrossRefGoogle Scholar
  11. 11.
    Nigavekar S, Sung L, Llanes M, El-Jawahri A, Lawrence T, Becker C, et al. 3H dendrimer nanoparticle organ/tumor distribution. Pharm Res. 2004;21(3):476–83.PubMedCrossRefGoogle Scholar
  12. 12.
    Wijagkanalan W, Kawakami S, Hashida M. Designing dendrimers for drug delivery and imaging: pharmacokinetic considerations. Pharm Res. 2011;28(7):1500–19.PubMedCrossRefGoogle Scholar
  13. 13.
    Zhou Q, Gallo J. The pharmacokinetic/pharmacodynamic pipeline: translating anticancer drug pharmacology to the clinic. AAPS J. 2011;13(1):111–20.PubMedCrossRefGoogle Scholar
  14. 14.
    Nestorov I. Whole body pharmacokinetic models. Clin Pharmacokinet. 2003;42(10):883–908.PubMedCrossRefGoogle Scholar
  15. 15.
    Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health. 1997;13(4):407–84.PubMedGoogle Scholar
  16. 16.
    Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10(7):1093–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Maiwald T, Timmer J. Dynamical modeling and multi-experiment fitting with PottersWheel. Bioinformatics. 2008;24(18):2037–43.PubMedCrossRefGoogle Scholar
  18. 18.
    Nestorov IA. Sensitivity analysis of pharmacokinetic and pharmacodynamic systems: I. A structural approach to sensitivity analysis of physiologically based pharmacokinetic models. J Pharmacokinet Pharmacodyn. 1999;27(6):577–96.CrossRefGoogle Scholar
  19. 19.
    Fenneteau F, Li J, Nekka F. Assessing drug distribution in tissues expressing P-glycoprotein using physiologically based pharmacokinetic modeling: identification of important model parameters through global sensitivity analysis. J Pharmacokinet Pharmacodyn. 2009;36(6):495–522.PubMedCrossRefGoogle Scholar
  20. 20.
    Nestorov IA, Aarons LJ, Rowland M. Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat: a sensitivity analysis. J Pharmacokinet Pharmacodyn. 1997;25(4):413–47.CrossRefGoogle Scholar
  21. 21.
    Longmire M, Choyke PL, Kobayashi H. Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats. Nanomedicine. 2008;3(5):703–17.PubMedCrossRefGoogle Scholar
  22. 22.
    Soo Choi H, Liu W, Misra P, Tanaka E, Zimmer JP, Itty Ipe B, et al. Renal clearance of quantum dots. Nat Biotech. 2007;25(10):1165–70.CrossRefGoogle Scholar
  23. 23.
    Boswell CA, Tesar DB, Mukhyala K, Theil F-P, Fielder PJ, Khawli LA. Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjugate Chem. 2010;21(12):2153–63.CrossRefGoogle Scholar
  24. 24.
    Kim B, Han G, Toley BJ, Kim C-k, Rotello VM, Forbes NS. Tuning payload delivery in tumour cylindroids using gold nanoparticles. Nat Nano. 2010;5(6):465–72.CrossRefGoogle Scholar
  25. 25.
    Varma MVS, Feng B, Obach RS, Troutman MD, Chupka J, Miller HR, et al. Physicochemical determinants of human renal clearance. J Med Chem. 2009;52(15):4844–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Owens 3rd DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307(1):93–102.PubMedCrossRefGoogle Scholar
  27. 27.
    Devine DV, Bradley AJ. The complement system in liposome clearance: can complement deposition be inhibited? Adv Drug Deliv Rev. 1998;32(1–2):19–29.PubMedCrossRefGoogle Scholar
  28. 28.
    Kobayashi H, Kawamoto S, Saga T, Sato N, Hiraga A, Konishi J, et al. Micro-MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: Reference to pharmacokinetic properties of dendrimer-based MR contrast agents. J Magn Reson Imaging. 2001;14(6):705–13.PubMedCrossRefGoogle Scholar
  29. 29.
    Kobayashi H, Sato N, Hiraga A, Saga T, Nakamoto Y, Ueda H, et al. 3D-micro-MR angiography of mice using macromolecular MR contrast agents with polyamidoamine dendrimer core with reference to their pharmacokinetic properties. Magn Reson Med. 2001;45(3):454–60.PubMedCrossRefGoogle Scholar
  30. 30.
    Hirom PC, Millburn P, Smith RL, Williams RT. Species variations in the threshold molecular-weight factor for the biliary excretion of organic anions. Biochem J. 1972;129(5):1071–7.PubMedGoogle Scholar
  31. 31.
    Kitchens KM, Kolhatkar RB, Swaan PW, Ghandehari H. Endocytosis inhibitors prevent poly(amidoamine) dendrimer internalization and permeability across Caco-2 Cells. Mol Pharm. 2008;5(2):364–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Covell DG, Barbet J, Holton OD, Black CD, Parker RJ, Weinstein JN. Pharmacokinetics of monoclonal immunoglobulin G1, F(ab')2, and Fab’ in mice. Cancer Res. 1986;46(8):3969–78.PubMedGoogle Scholar

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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