Effects of liposome-encapsulated drugs on macrophages: comparative activity of the diamidine 4',6-diamidino-2-phenylindole and the phenanthridinium salts ethidium bromide and propidium iodide.

Liposomes can be used for the intracellular delivery of drugs into macrophages. Previously, we developed a liposome-mediated macrophage 'suicide' technique based on the intraphagocytic accumulation of the liposomally delivered bisphosphonate clodronate. Later we found that the diamidine propamidine is even more effective in this approach. In the present study it is shown that liposome-encapsulated 4', 6-diamidino-2-phenylindole (L-DAPI), another well known DNA-binding diamidine, is the most effective drug in killing liver macrophages (Kupffer cells), when intravenously administered in rat. Compared to liposome-encapsulated propamidine (L-propamidine) it showed about 10-fold more activity on a molar basis. Furthermore, L-DAPI was found to induce cell death by inducing apoptosis. The structurally strongly related phenanthridinium salts ethidium bromide (EB) and propidium iodide (PI) exert marked differences in their efficacy. Whereas liposome-encapsulated PI (L-PI) was about 5 times more active in killing macrophages than L-propamidine, liposome-encapsulated EB (L-EB) showed a strongly reduced activity (10 times less than L-PI). As is shown here, PI remains mainly encapsulated in liposomes, while substantial amounts of EB leak out of liposomes. This may very well explain the differences in in vivo activity between L-EB and L-PI.