title: Pharmacokinetics of stealth versus conventional liposomes: effect of dose.
abstract: Liposomes which substantially avoid uptake into the mononuclear phagocyte system (MPS), termed Stealth liposomes, have recently been formulated (Allen, T.M. and Chonn, A., (1987) FEBS Lett. 223, 42-46). The pharmacokinetics of stealth liposomes as a function of liposome dose and a comparison to conventional liposome pharmacokinetics, was the subject of the present study. We have examined the tissue distribution of two different formulations of stealth liposomes, i.e., sphingomyelin:egg phosphatidylcholine:cholesterol:monosialoganglioside GM1 (SM:PC:CHOL:GM1) 1:1:1:0.2 and SM:PC:CHOL:polyethylene glycol distearoylphosphatidylethanolamine (PEG(1990)-DSPE) 1:1:1:0.2, and compared them with the tissue distributions seen for a liposomal formulation which is avidly removed from circulation by the cells of the MP system (PC:CHOL, 2:1). Tissue distribution in mice was examined over a 100-fold concentration range (0.1 to 10 mumol phospholipid/mouse) and at several time points over a 48 h time period. Liposome size ranged from 92-123 nm in diameter for all compositions. Clearance from blood of PC:CHOL liposomes following intravenous administration showed a marked dose dependence (i.e., saturation-type or Michaelis-Menten kinetics), with MPS uptake decreasing and % of injected dose in blood increasing as dose increased, over the entire dosage range. Injection of stealth liposomes, on the other hand, resulted in % of injected doses of liposomes in MPS, blood and carcass which were dose-independent and log-linear (first order kinetics) over the entire dosage range. The doses of stealth liposomes containing PEG(1900)-DSPE required for MPS saturation was higher than 10 mumol phospholipid/mouse or 400 mumol/kg. The dosage-independence of the pharmacokinetics of stealth liposomes and their lack of MPS saturation within the therapeutic dose range are two more assets, in addition to the prolonged circulation half-lives, leading towards their eventual use as drug delivery systems in the clinic.
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Canada.
authors.forename: T M
authors.initials: TM
authors.lastname: Allen
authors.forename: C
authors.initials: C
authors.lastname: Hansen
mesh_terms: D000818:Animals; D002784:Cholesterol; D004337:Drug Carriers; D005260:Female; D005677:G(M1) Ganglioside; D006207:Half-Life; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D009000:Monocytes / Q000378:metabolism*; D010586:Phagocytes / Q000378:metabolism*; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D012984:Software; D013109:Sphingomyelins
chemical_list: D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D013109:Sphingomyelins; C038089:1,2-distearoylphosphatidylethanolamine; D005677:G(M1) Ganglioside; D002784:Cholesterol