Research Paper

Pharmaceutical Research

, Volume 24, Issue 11, pp 2110-2119

First online:

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

  • Li WanAffiliated withDepartment of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey
  • , Shahriar PooyanAffiliated withDepartment of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey
  • , Peidi HuAffiliated withDepartment of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey
  • , Michael J. LeibowitzAffiliated withDepartment of Molecular Genetics, Microbiology & Immunology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical SchoolCancer Institute of New Jersey
  • , Stanley SteinAffiliated withDepartment of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey
  • , Patrick J. SinkoAffiliated withDepartment of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New JerseyCancer Institute of New JerseyEnvironmental and Occupational Health Science Institute Email author 

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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.

Key words

biodistribution HIV PEG-fMLF nanocarrier peritoneal macrophage pharmacokinetic