Pharmacokinetics of poly(hydroxyethyl-l-asparagine)-coated liposomes is superior over that of PEG-coated liposomes at low lipid dose and upon repeated administration.
'Stealth' liposomes with a poly(ethylene glycol) (PEG) coating are frequently studied for drug delivery and diagnostic purposes because of their prolonged blood circulation kinetics. However, several recent reports have demonstrated that PEG-liposomes are rapidly cleared at single low lipid doses (<1 micromol/kg) and upon repeated administration (time interval between the injections 5 days-4 weeks). Recently, poly(amino acid)-based stealth liposome coatings have been developed as alternative to the PEG-coating. In this study, the pharmacokinetic behavior of liposomes coated with the poly(amino acid) poly(hydroxyethyl-l-asparagine) (PHEA) was evaluated at low lipid doses and upon repeated administration in rats. Blood circulation times and hepatosplenic localization of PHEA-liposomes were assessed after intravenous injection. When administered at a dose of 0.25 micromol/kg or less, PHEA-liposomes showed significantly longer blood circulation times than PEG-liposomes. A second dose of PHEA-liposomes 1 week after the first injection was less rapidly cleared from the circulation than a second dose of PEG-liposomes. Although the mechanisms behind these observations are still not clear yet, the use of PHEA-liposomes appears beneficial when single low lipid doses and/or repeated dosing schedules are being applied.
Romberg
Birgit
B
Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands. b.romberg@pharm.uu.nl
Oussoren
Christien
C
Snel
Cor J
CJ
Carstens
Myrra G
MG
Hennink
Wim E
WE
Storm
Gert
G
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000818:Animals; D021461:Animals, Outbred Strains; D019540:Area Under Curve; D001216:Asparagine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002784:Cholesterol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems; D007275:Injections, Intravenous; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D010715:Phosphatidylglycerols / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
D008055:Lipids; D008081:Liposomes; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010715:Phosphatidylglycerols; D019275:Radiopharmaceuticals; C511917:poly(hydroxyethyl-L-asparagine); C038089:1,2-distearoylphosphatidylethanolamine; D015060:1,2-Dipalmitoylphosphatidylcholine; D011092:Polyethylene Glycols; D001216:Asparagine; D002784:Cholesterol