Etanidazole in pH-sensitive liposomes: design, characterization and in vitro/in vivo anti-Trypanosoma cruzi activity.

MORILLA MJ, MONTANARI J, FRANK FM, MALCHIODI EL, CORRAL R, PETRAY P & ROMERO EL.

JOURNAL OF CONTROLLED RELEASE

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2005 vol. 102 p. 599 - 607

0168-3659

In this work, the hydrophilic, low molecular weight and trypanocidal drug etanidazole (ETZ) was loaded in pH-sensitive liposomes (L-ETZ) made of dioleoyl-phosphatidylethanolamine: cholesteryl hemisuccinate (DOPE: CHEMS, 6: 4, mol:mol), of 380 nm size at 14% ETZ/total lipid (w/w) ratio. When uptake and intracellular fate of those pH-sensitive liposomes, loaded with the fluorophore/quencher pair HPTS/DPX, were followed by fluorescence microscopy, it resulted a fast delivery of the liposomal aqueous content into the cytosol of J774 macrophages. Both healthy and Trypanosoma cruzi RA strain infected-macrophages were capable of phagocytosing liposomes. Upon treating infected J774 macrophages with L-ETZ along 2 h, a 72 % of anti-amastigote activity (AA) vs 0 % AA for the same amount of free ETZ was found. Finally, three weekly endovenous administration of L-ETZ at 0.7 mg/kg dose provoked significant decrease in parasitemia levels of infected mice. In contrast, inoculation of a 150-fold higher dose of free ETZ failed in reducing the number of bloodstream forms of T. cruzi. Hence, these results point to the possibility of obtaining systems, such as L-ETZ vesicles, designed for selective delivery of drugs to the cytoplasm of phagocytic cells, and capable of enhancing the efficacy of molecules primarily considered poorly active.