In vivo antileishmanial action of Ir-(COD)-pentamidine tetraphenylborate on Leishmania donovani and Leishmania major mouse models

Ir-(COD)-pentamidine tetraphenylborate which has previously been studied on promastigote forms of Leishmania, was investigated for its antileishmanial properties compared with pentamidine used as reference compound. In vitro, the iridium complex had the same IC50 value on intracellular forms of Leis hmania as pentamidine (15 mu M) In vivo, the compound could not be injected intravenously due to the DMSO excipient so that the treatments were perfor med intraperitoneally or subcutaneously. On the L. donovani LV9/Balb/C mous e model, the iridium complex was not toxic after intraperitoneal treatment at 233 mg/kg/day x 5 or 147 mu moles/kg/day x 5, whereas all the mice died within five days when treated at the same dose with pentamidine isethionate . However, only 23 % of parasite suppression was observed with the iridium complex. On a L. major MON 74/Balb/C mouse model, susceptible to intravenou sly administered pentamidine at 6.7 mu moles/kg/day x 5 (54 % of parasite s uppression), the iridium complex exhibited 32 % of parasite suppression aft er a treatment at 76 mu moles/kg/day x 5 administered subcutaneously. This slight activity is of interest since pentamidine isethionate is not active under these conditions. Transmission electron microscopy of amastigotes fro m infected and treated mice show aggregation of ribosomal material, distens ion of the nuclear membrane and kDNA depolymerization. The mechanism of act ion therefore involves several targets: membranes, ribosomes and kDNA. Acco rding to our results, the Iridium complex is a suitable candidate to be enc apsulated in drug carriers such of liposomes or nanoparticles