Kupffer cell depletion by liposome-delivered drugs: Comparative activity of intracellular clodronate, propamidine, and ethylenediaminetetraacetic acid
Authors: N Van Rooijen
Journal: Hepatology (1996)

Macrophages such as Kupffer cells in the liver are phagocytic delivery and accumulation of the bisphosmultifunctional cells.They are involved in host defense phonate clodronate. 2 The mechanism of the approach mechanisms and have a regulatory role in many biomedis explained as follows (for a recent review, see Van ical processes.Their selective depletion, using liposome-Rooijen and Sanders 3 ): encapsulated drugs, forms a widely accepted approach 1.The natural fate of liposomes is phagocytosis.to studying their functional aspects in vivo.We have 2. Once ingested by macrophages, the phospholipid compared the Kupffer cell-depleting activities of lipobilayers of the liposomes are disrupted under the influsome-encapsulated clodronate, propamidine, and ethylence of lysosomal phospholipases.enediaminetetraacetic acid (EDTA) for this purpose.3. Clodronate, intracellularly released in this way, These molecules represent the drug families of bisphosdoes not easily escape from the cell by crossing the cell phonates, diamidines (or aromatic polyamidines), and polyaminopolycarboxylic acid-chelating agents, respec-membranes.tively.The Kupffer cell-depleting activity of the lipo-4.As a result, the released clodronate accumulates some-encapsulated antimicrobial drug propamidine exin the cell.ceeded that of clodronate by about a factor of 10.EDTA 5.At a certain intracellular clodronate concentraappeared to be inefficacious for depletion of Kupffer tion, irreversible damage causes the macrophage to be cells in the rat.(HEPATOLOGY 1996;23:1239-1243.)killed.6. Clodronate, released in the circulation from dead From an evolutionary point of view, macrophages macrophages or by leakage from liposomes, will not form an ancient cell population, representing the main cross cell membranes and has an extremely short halfhost defense mechanism until the development of the life in circulation and body fluids, 4 explaining the fact immune system.During evolution, macrophages also that nonphagocytic cells are not affected.acquired an important role in the regulation of immune Macrophage depletion has been confirmed by immureactions and in controlling cell functions of various nocytochemical 2 and electronmicroscopical 5 methods nonphagocytic cells, in addition to their scavenger funcand by functional assays. 2 Using this approach, the tion.As a consequence, in mammals, macrophages are multifunctional role of macrophages in mammals has multifunctional cells. 1 been confirmed.Selective in vivo depletion of macrophages is a widely Kupffer cells, the resident macrophages in the liver, accepted approach to investigating whether macroare highly sensitive to intravenously injected clodrophages are involved in any particular biomedical connate liposomes.Using the liposome-mediated macrotrol mechanism.Because the effects of the usual methphage ''suicide'' approach, it has been shown that Kupfods for macrophage depletion, such as treatment with fer cells are able to suppress, for instance, the silica, carrageenan, and antimacrophage antibodies, development of the extra-erythrocytic stages of Plasmowere neither selective nor complete, we developed a dium berghei 6 and the growth of (metastatic) tumor new approach, based on the liposome-mediated intracells in the liver. 7It was also shown that Kupffer cells are crucial for the functional differentiation of liverspecific natural killer cells. 8The influence of Kupffer Abbreviations: EDTA, ethylenediaminetetraacetic acid; PBS, phosphate-cells on various processes in the liver might well be buffered saline.mediated by their production and secretion of cyto-