Etanidazole in pH-sensitive liposomes: design, characterization and in vitro/in vivo anti-Trypanosoma cruzi activity.
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.
Morilla
Maria Jose
MJ
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.
Montanari
Jorge
J
Frank
Fernanda
F
Malchiodi
Emilio
E
Corral
Ricardo
R
Petray
Patricia
P
Romero
Eder Lilia
EL
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
D004337:Drug Carriers; D005079:Excipients; D008081:Liposomes; D014344:Trypanocidal Agents; D017341:Etanidazole