Langmuir monolayer study toward combined antileishmanian therapy involving amphotericin B and edelfosine.
In this work, the results of comparative studies on the effect of lysophospholipid analogue, edelfosine (ED), and its mixtures with the polyene antibiotic, amphotericin B (AmB), on model erythrocyte and parasite membranes are presented. Both compounds are known for their antileishmanian activity; however, the application of AmB is limited by its toxicity, while the treatment with alkyl-lysophospholipids (edelfosine) is expensive in addition to its lower therapeutic activity as compared to the polyene. An additional problem is the emergence of resistance to both groups of drugs. The foregoing facts inspired the investigations toward combined amphotericin B/alkyl-lysophospholipid therapy. In this aspect, the effect of edelfosine on model erythrocyte versus parasite membrane has been verified by the incorporation of the drug into binary sterol/phospholipid monolayer of the proportion corresponding to the respective cellular membrane. Afterward, amphotericin B/edelfosine mixtures of various proportions (1:9; 1:1, and 9:1) have been added into sterol/phospholipid model membranes in the concentration of 1, 5, and 10%. The interactions between amphotericin B and edelfosine in mixed monolayers have also been investigated. The obtained results indicate that differences in the organization of erythrocyte versus parasite membranes are of great importance for selectivity of edelfosine toward the parasite membrane. The mixtures of drugs practically do not modify the properties of model erythrocyte membrane; however, their incorporation in the parasite membrane is thermodynamically unfavorable and causes membrane destabilization. The strongest differences in the influence of drug mixtures on erythrocyte versus parasite model membrane occur for 1% content of 1:9 and 1:1 AmB/edelfosine mixture. Moreover, when edelfosine is combined with amphotericin B, a decrease in edelfosine concentration needed to induce a similar effect on parasite membranes as edelfosine alone does is observed. As a consequence of strong interactions between edelfosine and amphotericin B, the decrease of the activity of their mixtures on model membranes was found.
Hac-Wydro
Katarzyna
K
Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Kraków, Poland. hac@chemia.uj.edu.
Dynarowicz-Łatka
Patrycja
P
Zuk
Radosław
R
D000666:Amphotericin B / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D004910:Erythrocyte Membrane / Q000187:drug effects; D008567:Membranes, Artificial; D010742:Phospholipid Ethers / Q000737:chemistry* / Q000494:pharmacology; D010743:Phospholipids / Q000737:chemistry; D013261:Sterols / Q000737:chemistry; D013499:Surface Properties
D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D008567:Membranes, Artificial; D010742:Phospholipid Ethers; D010743:Phospholipids; D013261:Sterols; C026659:edelfosine; D000666:Amphotericin B