RESUMEN
The toxic effects of miltefosine on the epithelial cells of the gastrointestinal tract and its hemolytic action on erythrocytes have limited its use as an antileishmanial agent. As part of our search for new strategies to overcome the side effects of miltefosine during the treatment of leishmaniasis, we have developed stable miltefosine-loaded lipid nanoparticles in an attempt to reduce the toxic effects of the drug. We have evaluated lipid nanoparticles containing varying amounts of miltefosine and cholesterol, prepared by sonication, in terms of their physicochemical properties, preliminary stability, hemolytic potential toward erythrocytes, and cytotoxicity to macrophages and to promastigote and amastigote forms of Leishmania (L.) chagasi. Miltefosine loading into lipid nanoparticles was 100% for low drug concentrations (7.0 to 20.0mg/mL). Particle size decreased from 143nm (control) to between 43 and 69nm. From fluorescence studies, it was observed that the presence of miltefosine and cholesterol (below 103µM) promoted ordering effects in the phospholipid region of the nanoparticles. The formulation containing 15mg/mL miltefosine was stable for at least six months at 4°C and in simulated gastrointestinal fluids, and did not promote epithelial gastrointestinal irritability in Balb/C mice. When loaded into lipid nanoparticles, the hemolytic potential of miltefosine and its cytotoxicity to macrophages diminished, while its antiparasitic activity remained unaltered. The results suggested that miltefosine-loaded lipid nanoparticles may be promising for the treatment of leishmaniasis and might be suitable for oral and parenteral use.
Asunto(s)
Portadores de Fármacos/química , Nanopartículas/química , Fosforilcolina/análogos & derivados , Animales , Antiprotozoarios/administración & dosificación , Muerte Celular/efectos de los fármacos , Células Cultivadas , Estabilidad de Medicamentos , Eritrocitos/efectos de los fármacos , Enfermedades Gastrointestinales/tratamiento farmacológico , Enfermedades Gastrointestinales/patología , Hemólisis/efectos de los fármacos , Humanos , Lípidos/química , Macrófagos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Tamaño de la Partícula , Fosforilcolina/administración & dosificación , Células RAW 264.7RESUMEN
The fungus Penicillium sclerotiorum produces sclerotiorin, an orange compound closely related to the useful food coloring pigments produced by Monascus species. The high productivity, together with several biological activities reported for sclerotiorin highlights its potential application in food industry. In this work, sclerotiorin was obtained as the major metabolite produced in liquid fermentation by P. sclerotiorum standing for 30% of the fungal dry extract. Modulation of sclerotiorin color was accomplished by biotransformation using Beauveria bassiana generating a red derivative with 13.8% yield. Color modification was caused by fungal-mediated substitution of oxygen by nitrogen in the pyrone ring changing the molecule's chromophore. A derivative, 1-methyl sclerotiorin was synthesized from sclerotiorin using diazomethane and fed to B. bassiana. In this case, substituent at C-1 avoided heteroatom substitution. Sclerotiorin derivatives obtained in the present show the great potential of sclerotiorin derivatives as food colorants.