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

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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.

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Acknowledgements

This work was supported by grants AI 33789 and AI 51214 from National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA

    Li Wan, Shahriar Pooyan, Peidi Hu, Stanley Stein & Patrick J. Sinko

  2. Department of Molecular Genetics, Microbiology & Immunology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA

    Michael J. Leibowitz

  3. Cancer Institute of New Jersey, New Brunswick, New Jersey, 08903, USA

    Michael J. Leibowitz & Patrick J. Sinko

  4. Environmental and Occupational Health Science Institute, Piscataway, New Jersey, USA

    Patrick J. Sinko

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  1. Li Wan
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  2. Shahriar Pooyan
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Correspondence to Patrick J. Sinko.

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Wan, L., Pooyan, S., Hu, P. et al. Peritoneal Macrophage Uptake, Pharmacokinetics and Biodistribution of Macrophage-Targeted PEG-fMLF (N-Formyl-Methionyl-Leucyl-Phenylalanine) Nanocarriers for Improving HIV Drug Delivery. Pharm Res 24, 2110–2119 (2007). https://doi.org/10.1007/s11095-007-9402-5

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  • DOI: https://doi.org/10.1007/s11095-007-9402-5

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