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 output: Contribution to journalArticle

33 Citations (Scopus)

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 t 1/2 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.

Original languageEnglish (US)
Pages (from-to)2110-2119
Number of pages10
JournalPharmaceutical Research
Volume24
Issue number11
DOIs
StatePublished - Nov 2007
Externally publishedYes

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N-Formylmethionine Leucyl-Phenylalanine
Pharmacokinetics
Macrophages
Peritoneal Macrophages
Drug delivery
Polyethylene glycols
HIV
Pharmaceutical Preparations
Tissue Distribution
Tissue
Spleen
Fluorescence
Kidney
Liver
Peptides
Rats

Keywords

  • Biodistribution
  • HIV
  • PEG-fMLF nanocarrier
  • Peritoneal macrophage
  • Pharmacokinetic

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Peritoneal macrophage uptake, pharmacokinetics and biodistribution of macrophage-targeted PEG-fMLF (N-formyl-methionyl-leucyl-phenylalanine) nanocarriers for improving HIV drug delivery. / Wan, Li; Pooyan, Shahriar; Hu, Peidi; Leibowitz, Michael J; Stein, Stanley; Sinko, Patrick J.

In: Pharmaceutical Research, Vol. 24, No. 11, 11.2007, p. 2110-2119.

Research output: Contribution to journalArticle

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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 t 1/2 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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