ULTRASTRUCTURAL-CHANGES IN PARASITES INDUCED BY NANOPARTICLE-BOUND PENTAMIDINE IN A LEISHMANIA-MAJOR MOUSE MODEL

Drug targeting enhances drug efficacy. This principle was tested in th e treatment of an experimental visceral leishmaniasis. Using transmiss ion electron microscopy (TEM) we localized pentamidine-loaded polymeth acrylate nanoparticles in the liver of mice infected with leishmania m ajor and compared the ultrastructural changes in the parasites of thes e mice when they were treated with bound versus free pentamidine. Betw een days 13 and 17 after infection, loaded nanoparticles treated group were injected i.v. with 3 doses of 0.17 mg/kg bound pentamidine loade d on 2 x 10(11) nanospheres; control groups received 2 x 10(11) unload ed nanospheres. Drug reference control groups received five doses of 2 00 mg/kg pentavalent antimony (Glycantime(R)) or three doses oi free p entamidine (0.17 mg/kg or 2.28 mg/kg). Mice treated with bound pentami dine displayed a 77% reduction in their parasite burden versus the unt reated controls. Nanoparticles were located by TEM inside parasitized Kupffer cells, in the phagolysosomes without entering the Leishmania. The low dose of 0.17 mg/kg bound pentamidine damaged the Leishmania to the same extent as 2.28 mg/kg of free pentamidine (the usual dose in human chemotherapy). In the parasites inside the Kupffer cells, TEM sh owed a swollen mitochondrion with loss of cristae, destruction or frag mentation of the kinetoplast, loss of ribosomes and destruction of par asite structures except for the subpellicular microtubules. This study therefore shows that a dose of bound pentamidine 13 times smaller tha n the usual dose oi free pentamidine has a similar effect on the paras ite.