Comparative EPR spectroscopy analysis of amphotericin B and miltefosine interactions with Leishmania, erythrocyte and macrophage membranes
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2021
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Electron paramagnetic resonance (EPR) spectroscopy of spin labels was used to study the interactions of
amphotericin B (AmB) with the plasma membrane of Leishmania (L.) amazonensis promastigotes, human
erythrocytes and J774.A1 murine macrophages, in comparison with reported and novel data for miltefosine
(MIL). One of the objectives of this work is to look for the relationships between the activities of these two drugs
in the Leishmania parasite with their changes in the cell membrane. A spin-labeled stearic acid inserted into the
cell membranes showed strong interactions with putative AmB/sterol complexes, characterized by reductions in
molecular dynamics. The concentration of the drugs in the plasma membrane that reduced the cell population by
50%, and the membrane-water partition coefficient of the drugs, were assessed. These biophysical parameters
enabled estimates of possible therapeutic concentrations of these two drugs in the interstitial fluids of the tissues
to be made. AmB displayed higher affinity for the plasma membrane of L. amazonensis than for that of the
macrophage and erythrocyte, denoting a preference for a membrane that contains ergosterol. AmB also
demonstrated higher hemolytic potential than MIL for measurements on erythrocytes in both PBS and whole
blood. For MIL, the EPR technique detected membrane changes induced by the drug in the same concentration
range that inhibited the growth of parasites, but in the case of AmB, an 8-fold higher concentration of the IC50
was necessary to observe a reduction in membrane fluidity, suggesting a better localized effect of AmB on the
membrane. Taken together, the results demonstrate that the antiproliferative and cytotoxic effects of both drugs
are associated with changes in cell membranes.
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Amphotericin B, Miltefosine, Leishmania, Macrophages, Electron paramagnetic resonance
Citação
ALONSO, Lais; MENDANHA, Sebastião Antônio; GOMES, Rodrigo Saar; DORTA, Miriam Leandro; ALONSO, Antonio. Comparative EPR spectroscopy analysis of amphotericin B and miltefosine interactions with Leishmania, erythrocyte and macrophage membranes. European Journal of Pharmaceutical Sciences, Amsterdam, v. 163, e105859, 2021. DOI: 10.1016/j.ejps.2021.105859. Disponível em: https://www.sciencedirect.com/science/article/pii/S0928098721001615?via%3Dihub. Acesso em: 14 abr. 2023.