Manipulation of Kupffer cells by liposome encapsulated clodronate and propamidine - synergistic and antagonistic effects of liposomal phospholipids and drugs

Macrophages in the liver (Kupffer cells) can be depleted by a single intravenous injection with liposome encapsulated clodronate, an anionic bisphosphonate or by liposome encapsulated propamidine, a cationic diamidine. In the present study, it was investigated whether the efficacy of the liposome mediated depletion of Kupffer cells could be enhanced by modification of the phospholipid bilayers. The efficacy of liposome mediated depletion was evaluated by comparison of the percentages of ED2-positive Kupffer cells in the rat liver, depleted by the drugs encapsulated in the liposomes at different concentrations. It is demonstrated that anionic control liposomes, containing no drug at all and composed of phosphatidylcholine (PC), phosphatidylserine (PS) and cholesterol (C) in a molar ratio of 3:3:1, reduced the percentage of ED2-positive Kupffer cells in the rat liver to about 20% of their normal numbers. At certain drug concentrations, anionic liposomes are shown to be efficacious carriers for intraphagocytic delivery of clodronate, but not for propamidine. Optimal efficacy of the latter drug was achieved by encapsulation into neutral liposomes. Omission of cholesterol or mannosylation of the phospholipid bilayers did not improve the efficacy when compared to neutral liposomes. At high concentrations of encapsulated drugs, all liposome formulations induced a nearly complete depletion of Kupffer cells (>95%). (C) 1998 Elsevier Science B.V. All rights reserved.