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 mac rophages. Previously, we developed a liposome-mediated macrophage 'sui cide' technique based on the intraphagocytic accumulation of the lipos omally delivered bisphosphonate clodronate. Later we found that the di amidine propamidine is even more effective in this approach. In the pr esent study it is shown that liposome-encapsulated 4',6-diamidino-2-ph enylindole (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 in ducing apoptosis, The structurally strongly related phenanthridinium s alts ethidium bromide (EB) and propidium iodide (PI) exert marked diff erences 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 encapsulat ed in liposomes, while substantial amounts of EB leak out of liposomes . This may very well explain the differences in in vivo activity betwe en L-EB and L-PI. (C) 1998 Elsevier Science B.V. All rights reserved.