Drug targeting enhances
drug efficacy. This principle was tested in the treatment of an experimental
visceral leishmaniasis. Using transmission electron microscopy (TEM) we localized
pentamidine-loaded polymethocrylate nanoparticles in the liver of mice infected with Leishmania major and compared the ultrastructural changes in the parasites of these mice when they were treated with bound versus free
pentamidine. Between days 13 and 17 after
infection, loaded nanoparticles treated group were injected i.v. with 3 doses of 0.17 mg/kg bound
pentamidine loaded on 2 x 10(11)
nanospheres; control groups received 2 x 10(11) unloaded
nanospheres.
Drug reference control groups received five doses of 200 mg/kg pentavalent
antimony (
Glucantime) or three doses of free
pentamidine (0.17 mg/kg or 2.28 mg/kg). Mice treated with bound
pentamidine displayed a 77% reduction in their parasite burden versus the untreated controls. Nanoparticles were located by TEM inside parasitized Küpffer 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 Küpffer cells, TEM showed a swollen mitochondrian with loss of cristae, destruction or fragmentation of the kinetoplast, loss of ribosomes and destruction of parasite structures except for the subpellicular microtubules. This study therefore shows that a dose of bound
pentamidine 13 times smaller than the usual dose of free
pentamidine has a similar effect on the parasite.