Peritoneal macrophage uptake, pharmacokinetics and biodistribution of macrophage-targeted PEG-fMLF (N-formyl-methionyl-leucyl-phenylalanine) nanocarriers for improving HIV drug delivery.
OBJECTIVE
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 t(1/2) of PEG(5K) by threefold but decreased the t(1/2) of PEG(20K) 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.
Wan
Li
L
Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey 08854, USA.
Pooyan
Shahriar
S
Hu
Peidi
P
Leibowitz
Michael J
MJ
Stein
Stanley
S
Sinko
Patrick J
PJ
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D004337:Drug Carriers; D005260:Female; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D049329:Nanostructures; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D019380:Anti-HIV Agents; D004337:Drug Carriers; D011092:Polyethylene Glycols; D009240:N-Formylmethionine Leucyl-Phenylalanine
N Engl J Med. 2004 Apr 29;350(18):1872-80
15115833
Int J Pharm. 2000 Mar 30;198(1):83-95
10722953
N Engl J Med. 1985 Dec 12;313(24):1493-7
2999591
Science. 1988 Feb 5;239(4840):586-92
3277272
J Virol. 1991 Jan;65(1):356-63
1985204
Bioconjug Chem. 1995 Jan-Feb;6(1):62-9
7711105
Pharmacol Ther. 1997;74(1):73-102
9336017
Nature. 1998 Apr 30;392(6679 Suppl):5-10
9579855
JAMA. 1998 Jul 1;280(1):67-71
9660366
Cancer Chemother Pharmacol. 1998;42(5):407-14
9771956
Antivir Chem Chemother. 1998 May;9(3):187-203
9875399
Bioconjug Chem. 1999 Jul-Aug;10(4):638-46
10411462
Infect Immun. 1984 Nov;46(2):448-52
6500699
J Leukoc Biol. 2003 Nov;74(5):635-41
12960232
Adv Drug Deliv Rev. 2003 Sep 26;55(10):1261-77
14499706
Adv Drug Deliv Rev. 2003 Feb 10;55(2):217-50
12564978
Antiviral Res. 2002 Aug;55(2):209-25
12103427
Curr Pharm Des. 2002;8(6):433-40
12069380
Adv Drug Deliv Rev. 2002 Jun 17;54(4):459-76
12052709
Nat Med. 2002 May;8(5):522-6
11984599
Bioconjug Chem. 2002 Mar-Apr;13(2):216-23
11906258
J Control Release. 2002 Feb 19;79(1-3):29-40
11853916
BioDrugs. 2001;15(7):419-29
11520253
Clin Pharmacokinet. 2001;40(7):539-51
11510630
J Control Release. 2001 Jul 6;74(1-3):159-71
11489492
Science. 2001 Jul 6;293(5527):58-9
11441170
J Control Release. 2001 May 14;72(1-3):217-24
11390000
Nature. 2001 Apr 19;410(6831):995-1001
11309630
Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):658-63
11136236
AIDS. 2001 Jan 5;15(1):17-22
11192864
J Control Release. 2000 Dec 3;69(3):327-35
11102673
Eur J Pharm Sci. 2000 Oct;11 Suppl 2:S81-91
11033430
J Leukoc Biol. 2000 Sep;68(3):345-50
10985250
AIDS. 2000 Mar 10;14(4):357-66
10770537