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 Chona, 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 GM 1 (SM: PC: CHOL: GM 1) 1:1:1:0.2 and SM: PC: CHOL: polyethylene glycol distearoylphosphatidylethanolamine (PEG(1900)-DSPE) 1:1:1:0.2, and compared them with the tissue distributions seen for a lipsomal 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 10μmol 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 intravensous adminstration 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 liposome, 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 10μ mol phospholipid/mouse or 400 μmol/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.