Avaliação da eficácia de diamidínicos fluorados e nanopartículas metálicas na leishmaniose cutânea

Abstract

In view of the need to explore new treatment options for Cutaneous Leishmaniasis (LC), we evaluated the efficacy of fluorinated analogues of pentamidine [1,5-bis (4-amidinophenoxy) - 3,3-difluoropentane-5A6F; and 1,5-bis (4-amidinophenoxy) -2,2,3,3,4,4-hexafluoropentane- 5A6F], a drug used in the treatment of LTA, besides synthesizing, characterizing and evaluating the efficacy of bioactive inorganic nanomaterials ( NIB) of niobium oxides (Nb) and tantalum (Ta) oxides, nanoformulations with therapeutic properties still unknown. Were performed in vitro evaluations (efficacy against promastigotes and amastigotes, and cytotoxicity in murine macrophages) and in vivo (clinical and parasitological evolution of LC in mice and hamsters) evaluations against Leishmania (Leishmania) amazonensis e L. (Viannia) guyanensis. Inhibitory concentration 50 (IC50) of fluorinated analogues against L. (L.) amazonensis promastigotes after 24 hours (h) of treatment was 71.66 and 49.50 nM/mL for 5A2F and 5A6F, respectively, while the positive control (C+) was 47.94 nM/mL. The IC50 for L. (V.) guyanensis after 24 h was 17.53, 45.17 and 41.03 nM/mL for C+, 5A2F and 5A6F, respectively, evidencing the higher sensitivity of this species to the diamidines. The efficacy against amastigotes, measured from the infection rate of macrophages (MØ), of L. (L.) amazonensis after 48 h exposure to 50 nM/mL was greater than 70% for C+ and 5A2F, while against L. (V.) guyanensis, under the same conditions and exposure period, was higher than 90%. There was no significant difference between the evolution of LC in mice infected with L. (L.) amazonensis treated with diamidines and negative control (C-), while in infected mice with L. (V.) guyanensis was observed clinical cure in all treatments, although no parasitological cure was observed. The NIB presented size of 76.53 nm and a ζ potential of 19.63 mV for NIB-Nb, and 19.22 nm and potential ζ of 22.57 mV for NIB-Ta, after the synthesis. The NIB-Ta showed efficacy against promastigotes of L. (L.) amazonensis and L. (V.) guyanensis, whereas NIB-Nb stimulated the replication of L. (L.) amazonensis, surpassing the parasite number of negative control in the majority of concentrations tested. The effectiveness of NIB against amastigotes was better than those observed for C+ in all treatments after 48 hours of exposure, especially the effect on L. (V.) guyanensis, maintaining efficacy higher than 90% in treatments with 6.00 μM/mL. The evolution of LC in hamsters infected with L. (L.) amazonensis and by L. (V.) guyanensis was not satisfactory after treatment using NIB, since they presented inflammatory properties in the affected tissue, which increased the increase and severity of the lesions. It was demonstrated during the study that uninfected animals also presented local damage and inflammation after consecutive NIB administrations, a fact that explains the inefficacy and that may encourage future studies. The results with the diamidine analogs were more expressive in the experimental treatments, but the in vitro NIB results can still be explored in future studies against LC.