Administration of liposomal agents and blood clearance capacity of the mononuclear phagocyte system

Abstract

As liposomes are cleared from the circulation to a substantial extent by the phagocytic cells of the mononuclear phagocyte system (MPS), there is a question whether administration of liposome-based therapeutic agents interferes with clearance of infectious organisms by the MPS from blood. In the present study, at first the effect of administration of three types of empty liposomes (devoid of drug), differing in blood residence time, on carbon clearance and bacterial clearance from blood was studied with mice. Classical liposomes (LIP A) and placebo liposomes with lipid composition as in AmBisome (LIP B) or as in Doxil (LIP C) were used. Liposomes were administered intravenously as a single dose. Second, the effect of multiple-dose administration of AmBisome on bacterial blood clearance was studied with rats. AmBisome was administered with two different dosage schedules. The blood clearance capacity of the MPS was monitored at different time points after the last liposome injection. It was shown that the carbon blood clearance capacity of the MPS was impaired only at a high lipid dose of empty classical liposomes. The bacterial blood clearance capacity was never impaired, not even after prolonged treatment with AmBisome administered in a clinically relevant regimen.

FIG. 1

Residence of ⁶⁷Ga-DF-labeled liposomes in blood after single-dose administration (i.v.) in mice. Only the time points at which >90, 50, or 10% of injected liposomes are present in blood are indicated (n = 3 per time point). ○, LIP A (classical liposomes) at 80 μmol of lipid/kg; •, LIP A at 400 μmol of lipid/kg; ▪, LIP B (placebo liposomes with lipid composition as in AmBisome) at 400 μmol of lipid/kg; ▴, LIP C (placebo liposomes with lipid composition as in Doxil) at 400 μmol of lipid/kg.

FIG. 2

Clearance of carbon from blood in mice after single-dose administration (i.v.) of empty liposomes at 400 μmol of lipid/kg. LIP A, classical liposomes; LIP B, placebo liposomes with lipid composition as in AmBisome; LIP C, placebo liposomes with lipid composition as in Doxil. Carbon clearance from blood was determined at the time that >90% (a), 50% (b), or 10% (c) of liposomes were present in blood. Results are expressed as the mean percentages (n = 6 per time point per treatment) of clearance ± standard deviations in mice treated with liposomes (░⃞) or buffer (). ∗, P ≤ 0.001 versus buffer-treated mice.

FIG. 3

Clearance of K. pneumoniae from blood in mice after single-dose administration (i.v.) of empty liposomes at 400 μmol of lipid/kg. For explanations of symbols and panels, see the legend to Fig. 2.

FIG. 4

Clearance of S. aureus from blood in mice after single-dose administration (i.v.) of empty liposomes at 400 μmol of lipid/kg. For explanations of symbols and panels, see the legend to Fig. 2.

FIG. 5

Effect of AmBisome (▪) for 5 consecutive days at 5 mg of AMB/kg · day (equivalent to 50 μmol of lipid/kg · day) on clearance of K. pneumoniae from blood in rats. Bacterial blood clearance was determined at 24 as well as 72 h after the last injection of liposomes. Controls were treated with placebo liposomes (□) or buffer (○). Results are expressed as the geometric means of numbers of viable bacteria ± standard deviations for 10 rats per time point per treatment.

FIG. 6

Effect of AmBisome (▪) for 10 consecutive days at 5 mg of AMB/kg · day (equivalent to 50 μmol of lipid/kg · day) on clearance of K. pneumoniae from blood in rats. For explanations of open symbols, see the legend to Fig. 5.