title: Etanidazole in pH-sensitive liposomes: design, characterization and in vitro/in vivo anti-Trypanosoma cruzi activity.
abstract: In this work, the hydrophilic, low molecular weight and trypanocidal drug etanidazole (ETZ) was loaded in pH-sensitive liposomes (L-ETZ). Liposomes were made of dioleoyl-phosphatidylethanolamine: cholesteryl hemisuccinate (DOPE:CHEMS, 6:4, mol:mol), of 380 nm size at 14% ETZ/total lipid (w/w) ratio. To follow their uptake and intracellular fate by fluorescence microscopy, pH-sensitive liposomes were loaded with the fluorophore/quencher pair HPTS/DPX. A fast and massive delivery of the liposomal aqueous content into the cytosol of murine J774 macrophages was observed. L-ETZ vesicles were phagocytosed by both uninfected and Trypanosoma cruzi-infected macrophages. A 72% of anti-amastigote activity (AA) was demonstrated on L-ETZ-treated J774 cells, whereas the same dose of free ETZ rendered 0% AA. Endovenous administration of L-ETZ at 14 microg/mouse dose provoked significant decrease in parasitemia levels of T. cruzi-infected mice. Conversely, inoculation of a 180-fold higher dose of free ETZ failed in reducing the number of bloodstream trypomastigotes. Hence, these results point to develop systems, such as L-ETZ, designed for selective delivery of drugs to the cytoplasm of phagocytic cells, thus enhancing the efficacy of molecules considered poorly active.
authors.affiliation: Laboratorio de Diseño de Estrategias de Targeting de Drogas (LDTD), Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Roque Saenz Peña 180, Bernal B1876BXD, Buenos Aires, Argentina.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Morilla
authors.forename: Jorge
authors.initials: J
authors.lastname: Montanari
authors.forename: Fernanda
authors.initials: F
authors.lastname: Frank
authors.forename: Emilio
authors.initials: E
authors.lastname: Malchiodi
authors.forename: Ricardo
authors.initials: R
authors.lastname: Corral
authors.forename: Patricia
authors.initials: P
authors.lastname: Petray
authors.forename: Eder Lilia
authors.initials: EL
authors.lastname: Romero
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004337:Drug Carriers; D004705:Endocytosis / Q000187:drug effects; D017341:Etanidazole / Q000008:administration & dosage* / Q000494:pharmacology*; D005079:Excipients; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D010316:Particle Size; D010587:Phagocytosis / Q000187:drug effects; D014344:Trypanocidal Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000648:ultrastructure; D014352:Trypanosomiasis / Q000188:drug therapy / Q000469:parasitology
chemical_list: D004337:Drug Carriers; D005079:Excipients; D008081:Liposomes; D014344:Trypanocidal Agents; D017341:Etanidazole