Interaction of miltefosine with intercellular membranes of stratum corneum and biomimetic lipid vesicles.
Miltefosine (MT) is an alkylphospholipid approved for breast cancer metastasis and visceral leishmaniasis treatments, although the respective action mechanisms at the molecular level remain poorly understood. In this work, the interaction of miltefosine with the lipid component of stratum corneum (SC), the uppermost skin layer, was studied by electron paramagnetic resonance (EPR) spectroscopy of several fatty acid spin-labels. In addition, the effect of miltefosine on (i) spherical lipid vesicles of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and (ii) lipids extracted from SC was also investigated, by EPR and time-resolved polarized fluorescence methods. In SC of neonatal Wistar rats, 4% (w/w) miltefosine give rise to a large increase of the fluidity of the intercellular membranes, in the temperature range from 6 to about 50°C. This effect becomes negligible at temperatures higher that ca. 60°C. In large unilamelar vesicles of DPPC no significant changes could be observed with a miltefosine concentration 25% molar, in close analogy with the behavior of biomimetic vesicles prepared with bovine brain ceramide, behenic acid and cholesterol. In these last samples, a 25 mol% molar concentration of miltefosine produced only a modest decrease in the bilayer fluidity. Although miltefosine is not a feasible skin permeation enhancer due to its toxicity, the information provided in this work could be of utility in the development of a MT topical treatment of cutaneous leishmaniasis.
Instituto de Física, Universidade Federal de Goiás, Goiânia, GO, Brazil. alonso@if.ufg.br
Lais
L
Alonso
Sebastião Antônio
SA
Mendanha
Cássia Alessandra
CA
Marquezin
Marina
M
Berardi
Amando Siuiti
AS
Ito
A Ulises
AU
Acuña
Antonio
A
Alonso
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D040761:Biomimetic Materials; D002417:Cattle; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D005227:Fatty Acids / Q000378:metabolism; D005454:Fluorescence Polarization; D008560:Membrane Fluidity / Q000187:drug effects; D008563:Membrane Lipids / Q000378:metabolism*; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D013113:Spin Labels; D013696:Temperature
D000970:Antineoplastic Agents; D002518:Ceramides; D005227:Fatty Acids; D008563:Membrane Lipids; D013113:Spin Labels; D010767:Phosphorylcholine; D015060:1,2-Dipalmitoylphosphatidylcholine; C039128:miltefosine; D002784:Cholesterol; C007547:behenic acid