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 language | English (US) |
|---|---|
| Pages (from-to) | 2110-2119 |
| Number of pages | 10 |
| Journal | Pharmaceutical Research |
| Volume | 24 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2007 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Peritoneal macrophage uptake, pharmacokinetics and biodistribution of macrophage-targeted PEG-fMLF (N-formyl-methionyl-leucyl-phenylalanine) nanocarriers for improving HIV drug delivery
AU - Wan, Li
AU - Pooyan, Shahriar
AU - Hu, Peidi
AU - Leibowitz, Michael J
AU - Stein, Stanley
AU - Sinko, Patrick J.
PY - 2007/11
Y1 - 2007/11
N2 - 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.
AB - 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.
KW - Biodistribution
KW - HIV
KW - PEG-fMLF nanocarrier
KW - Peritoneal macrophage
KW - Pharmacokinetic
UR - http://www.scopus.com/inward/record.url?scp=34848891527&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34848891527&partnerID=8YFLogxK
U2 - 10.1007/s11095-007-9402-5
DO - 10.1007/s11095-007-9402-5
M3 - Article
C2 - 17701325
AN - SCOPUS:34848891527
VL - 24
SP - 2110
EP - 2119
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 11
ER -