Pharmacokinetics of stealth versus conventional liposomes: effect of dose

Biochim Biophys Acta. 1991 Sep 30;1068(2):133-41. doi: 10.1016/0005-2736(91)90201-i.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol
  • Drug Carriers
  • Female
  • G(M1) Ganglioside
  • Half-Life
  • Liposomes / chemistry
  • Liposomes / pharmacokinetics*
  • Mice
  • Monocytes / metabolism*
  • Phagocytes / metabolism*
  • Phosphatidylcholines
  • Phosphatidylethanolamines
  • Software
  • Sphingomyelins

Substances

  • Drug Carriers
  • Liposomes
  • Phosphatidylcholines
  • Phosphatidylethanolamines
  • Sphingomyelins
  • 1,2-distearoylphosphatidylethanolamine
  • G(M1) Ganglioside
  • Cholesterol