Pharmaceutical Research

, Volume 24, Issue 11, pp 2110–2119

Peritoneal Macrophage Uptake, Pharmacokinetics and Biodistribution of Macrophage-Targeted PEG-fMLF (N-Formyl-Methionyl-Leucyl-Phenylalanine) Nanocarriers for Improving HIV Drug Delivery

  • Li Wan
  • Shahriar Pooyan
  • Peidi Hu
  • Michael J. Leibowitz
  • Stanley Stein
  • Patrick J. Sinko
Research Paper

Abstract

Purpose

To assess in vivo macrophage targeting potential of PEG-fMLF nanocarriers and to investigate their biodistribution, peritoneal macrophage uptake, and pharmacokinetics.

Methods

Multiple copies of fMLF were conjugated to purchased and novel (branched, peptide-based) PEG nanocarriers. Peritoneal macrophage uptake was evaluated in mice 4 hours after IP administration of fluorescence-labeled PEG-fMLF nanocarriers. Pharmacokinetics and biodistribution were determined in rats after IV administration of tritiated PEG-fMLF nanocarriers.

Results

Attachment of one, two, or four fMLF copies increased uptake in macrophages by 3.8-, 11.3-, and 23.6-fold compared to PEG without fMLF. Pharmacokinetic properties and tissue distribution also differed between nanocarriers with and without fMLF. Attachment of fMLF residues increased the t1/2 of PEG5K by threefold but decreased the t1/2 of PEG20K by 40%. Attachment of fMLF increased accumulation of nanocarriers into macrophages of liver, kidneys and spleen. However, on a molar basis, penetration was equivalent suggesting nanocarrier size and targeting moieties are important determinants.

Conclusions

These results demonstrate the feasibility for targeting macrophages, a primary HIV reservoir site. However, these studies also suggest that balancing peripheral tissue penetration (a size-dependent phenomenon) versus target cell uptake specificity remains a challenge to overcome.

Key words

biodistribution HIV PEG-fMLF nanocarrier peritoneal macrophage pharmacokinetic 

References

  1. 1.
    A. M. Vandamme, K. Van Vaerenbergh, and E. De Clercq. Anti-human immunodeficiency virus drug combination strategies. Antivir. Chem. Chemother. 9:187–203 (1998).PubMedGoogle Scholar
  2. 2.
    D. R. Bangsberg, F. M. Hecht, E. D. Charlebois, A. R. Zolopa, M. Holodniy, L. Sheiner, J. D. Bamberger, M. A. Chesney, and A. Moss. Adherence to protease inhibitors, HIV-1 viral load, and development of drug resistance in an indigent population. AIDS 14:357–366 (2000).PubMedCrossRefGoogle Scholar
  3. 3.
    L. K. Schrager and M. P. D’Souza. Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy. JAMA 280:67–71 (1998).PubMedCrossRefGoogle Scholar
  4. 4.
    D. D. Richman. HIV chemotherapy. Nature 410:995–1001 (2001).PubMedCrossRefGoogle Scholar
  5. 5.
    R. Langer. Drug delivery and targeting. Nature 392:5–10 (1998).PubMedGoogle Scholar
  6. 6.
    R. Langer. Drug delivery. Drugs on target. Science 293:58–59 (2001).PubMedCrossRefGoogle Scholar
  7. 7.
    V. P. Torchilin. Drug targeting. Eur. J. Pharm. Sci. 11(Suppl 2):S81–S91 (2000).PubMedCrossRefGoogle Scholar
  8. 8.
    H. Schuitemaker, N. A. Kootstra, R. E. de Goede, F. de Wolf, F. Miedema, and M. Tersmette. Monocytotropic human immunodeficiency virus type 1 (HIV-1) variants detectable in all stages of HIV-1 infection lack T-cell line tropism and syncytium-inducing ability in primary T-cell culture. J. Virol. 65:356–363 (1991).PubMedGoogle Scholar
  9. 9.
    S. Aquaro, R. Calio, J. Balzarini, M. C. Bellocchi, E. Garaci, and C. F. Perno. Macrophages and HIV infection: therapeutical approaches toward this strategic virus reservoir. Antiviral Res. 55:209 (2002).PubMedCrossRefGoogle Scholar
  10. 10.
    F. Ahsan, I. P. Rivas, M. A. Khan, and A. I. Torres Suarez. Targeting to macrophages: role of physicochemical properties of particulate carriers—liposomes and microspheres—on the phagocytosis by macrophages. J. Control Release. 79:29–40 (2002).PubMedCrossRefGoogle Scholar
  11. 11.
    T. Igarashi, C. R. Brown, Y. Endo, A. Buckler-White, R. Plishka, N. Bischofberger, V. Hirsch, and M. A. Martin. Macrophage are the principal reservoir and sustain high virus loads in rhesus macaques after the depletion of CD4+ T cells by a highly pathogenic simian immunodeficiency virus/HIV type 1 chimera (SHIV): Implications for HIV-1 infections of humans. Proc. Natl. Acad. Sci. U S A 98:658 (2001).PubMedCrossRefGoogle Scholar
  12. 12.
    D. Marras, L. A. Bruggeman, F. Gao, N. Tanji, M. M. Mansukhani, A. Cara, M. D. Ross, G. L. Gusella, G. Benson, V. D. D’Agati, B. H. Hahn, M. E. Klotman, and P. E. Klotman. Replication and compartmentalization of HIV-1 in kidney epithelium of patients with HIV-associated nephropathy. Nat. Med. 8:522–526 (2002).PubMedCrossRefGoogle Scholar
  13. 13.
    R. W. Price, B. Brew, J. Sidtis, M. Rosenblum, A. C. Scheck, and P. Cleary. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science 239:586–592 (1988).PubMedCrossRefGoogle Scholar
  14. 14.
    D. D. Ho, T. R. Rota, R. T. Schooley, J. C. Kaplan, J. D. Allan, J. E. Groopman, L. Resnick, D. Felsenstein, C. A. Andrews, and M. S. Hirsch. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N. Engl. J. Med. 313:1493–1497 (1985).PubMedCrossRefGoogle Scholar
  15. 15.
    J. Stebbing, B. Gazzard, and D. C. Douek. Where does HIV live? N. Engl. J. Med. 350:1872–1880 (2004).PubMedCrossRefGoogle Scholar
  16. 16.
    S. M. Crowe and S. Sonza. HIV-1 can be recovered from a variety of cells including peripheral blood monocytes of patients receiving highly active antiretroviral therapy: a further obstacle to eradication. J. Leukoc. Biol. 68:345–350 (2000).PubMedGoogle Scholar
  17. 17.
    S. Sonza, H. P. Mutimer, R. Oelrichs, D. Jardine, K. Harvey, A. Dunne, D. F. Purcell, C. Birch, and S. M. Crowe. Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy. AIDS 15:17–22 (2001).PubMedCrossRefGoogle Scholar
  18. 18.
    S. Pooyan, B. Qiu, M. M. Chan, D. Fong, P. J. Sinko, M. J. Leibowitz, and S. Stein. Conjugates bearing multiple formyl-methionyl peptides display enhanced binding to but not activation of phagocytic cells. Bioconjug. Chem. 13:216–223 (2002).PubMedCrossRefGoogle Scholar
  19. 19.
    E. R. Prossnitz and R. D. Ye. The N-formyl peptide receptor: a model for the study of chemoattractant receptor structure and function. Pharmacol. Ther. 74:73–102 (1997).PubMedCrossRefGoogle Scholar
  20. 20.
    B. Burke and C. E. Lewis. The macrophage. Oxford University Press, Oxford, New York, 2002.Google Scholar
  21. 21.
    B. Vernon-Roberts. The macrophage. University Press, Cambridge [Eng.], 1972.Google Scholar
  22. 22.
    P. C. Leijh, T. L. van Zwet, M. N. ter Kuile, and R. van Furth. Effect of thioglycolate on phagocytic and microbicidal activities of peritoneal macrophages. Infect. Immun. 46:448–452 (1984).PubMedGoogle Scholar
  23. 23.
    S. Maesaki. Drug delivery system of anti-fungal and parasitic agents. Curr. Pharm. Des. 8:433–440 (2002).PubMedCrossRefGoogle Scholar
  24. 24.
    A. Kozlowski and J. M. Harris. Improvements in protein PEGylation: pegylated interferons for treatment of hepatitis C. J. Control. Release 72:217–224 (2001).PubMedCrossRefGoogle Scholar
  25. 25.
    J. M. Harris, N. E. Martin, and M. Modi. Pegylation: a novel process for modifying pharmacokinetics. Clin. Pharmacokinet. 40:539–551 (2001).PubMedCrossRefGoogle Scholar
  26. 26.
    A. Kozlowski, S. A. Charles, and J. M. Harris. Development of pegylated interferons for the treatment of chronic hepatitis C. BioDrugs 15:419–429 (2001).PubMedCrossRefGoogle Scholar
  27. 27.
    C. D. Conover, R. B. Greenwald, A. Pendri, C. W. Gilbert, and K. L. Shum. Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker. Cancer Chemother. Pharmacol. 42:407–414 (1998).PubMedCrossRefGoogle Scholar
  28. 28.
    R. B. Greenwald. PEG drugs: an overview. J. Control. Release 74:159–171 (2001).PubMedCrossRefGoogle Scholar
  29. 29.
    R. B. Greenwald, Y. H. Choe, J. McGuire, and C. D. Conover. Effective drug delivery by PEGylated drug conjugates. Adv. Drug Deliv. Rev. 55:217–250 (2003).PubMedCrossRefGoogle Scholar
  30. 30.
    M. J. Roberts, M. D. Bentley, and J. M. Harris. Chemistry for peptide and protein PEGylation. Adv. Drug Deliv. Rev. 54:459–476 (2002).PubMedCrossRefGoogle Scholar
  31. 31.
    P. Caliceti and F. M. Veronese. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv. Drug Deliv. Rev. 55:1261–1277 (2003).PubMedCrossRefGoogle Scholar
  32. 32.
    J. M. Harris. Poly(ethylene glycol) chemistry: biotechnical and biomedical applications. Plenum, New York, 1991.Google Scholar
  33. 33.
    M. R. Sherman, L. D. Williams, M. C. P. Saifer, J. A. French, L. W. Kwak, and J. J. Oppenheim. Conjugation of high, molecular weight poly(ethylene glycol) to cytokines: granulocyte-macrophage colony stimulating factors as model substrates. ACS, Washington, DC, 1997.Google Scholar
  34. 34.
    P. Caliceti, O. Schiavon, and F. M. Veronese. Biopharmaceutical properties of uricase conjugated to neutral and amphiphilic polymers. Bioconjug. Chem. 10:638–646 (1999).PubMedCrossRefGoogle Scholar
  35. 35.
    I. L. Koumenis, Z. Shahrokh, S. Leong, V. Hsei, L. Deforge, and G. Zapata. Modulating pharmacokinetics of an anti-interleukin-8 F(ab′)(2) by amine-specific PEGylation with preserved bioactivity. Int. J. Pharm. 198:83–95 (2000).PubMedCrossRefGoogle Scholar
  36. 36.
    F. M. Veronese, P. Caliceti, and O. Schiavon. Branched and linear poly(ethylene glycol): Influence of the polymer structure on enzymological, pharmacokinetic, and immunological properties of protein conjugates. J. Bioact. Compat. Polym. 12:196–207 (1997).Google Scholar
  37. 37.
    C. Monfardini, O. Schiavon, P. Caliceti, M. Morpurgo, J. M. Harris, and F. M. Veronese. A branched monomethoxypoly(ethylene glycol) for protein modification. Bioconjug. Chem. 6:62–69 (1995).PubMedCrossRefGoogle Scholar
  38. 38.
    S. Crowe, T. Zhu, and W. A. Muller. The contribution of monocyte infection and trafficking to viral persistence, and maintenance of the viral reservoir in HIV infection. J. Leukoc. Biol. 74:635 (2003).PubMedCrossRefGoogle Scholar
  39. 39.
    J. Hu, H. Liu, and L. Wang. Enhanced delivery of AZT to macrophages via acetylated LDL. J. Control. Release 69:327–335 (2000).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Li Wan
    • 1
  • Shahriar Pooyan
    • 1
  • Peidi Hu
    • 1
  • Michael J. Leibowitz
    • 2
    • 3
  • Stanley Stein
    • 1
  • Patrick J. Sinko
    • 1
    • 3
    • 4
  1. 1.Department of Pharmaceutics, Ernest Mario School of Pharmacy, RutgersThe State University of New JerseyPiscatawayUSA
  2. 2.Department of Molecular Genetics, Microbiology & ImmunologyUniversity of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical SchoolPiscatawayUSA
  3. 3.Cancer Institute of New JerseyNew BrunswickUSA
  4. 4.Environmental and Occupational Health Science InstitutePiscatawayUSA

Personalised recommendations