Estudo pré-clínico com complexos e nanopartículas metálicas para o tratamento da leishmaniose cutânea

Abstract

Tegumentary Leishmaniasis is an infectious disease that presents different clinical manifestations, caused by protozoa of the Leishmania genus. Currently, meglumine antimoniate is the first-choice treatment in Brazil and pentamidine isethionate, amphotericin B and liposomal amphotericin B make part of the second-choice drugs. Due to the limited efficacy and high toxicity of these drugs, there is a need for studies to develop drugs that have greater efficacy and less toxicity. In this sense, medicinal inorganic chemistry has been arousing the interest of the scientific community, given its studies with metallic ions that have shown promising therapeutic activities. The present study aimed to evaluate antileishmanial in vitro and in vivo activity of metal complexes and nanoparticles. Thus, in vitro evaluations of antileishmanial activity in promastigote and amastigote forms were carried out, as well as the evaluation of cytotoxicity in murine peritoneal macrophages and human monocytes. The substances that showed promise in the in vitro assays were selected for the in vivo assays, in which the antileishmanial activity of the copper (I) complex and tantalum nanoparticles (TaNPs) was evaluated in hamsters and mice infected with Leishmania spp., respectively. The obtained results demonstrated that in the in vitro cytotoxicity assays the copper (I) complex and the palladium (II) complexes presented moderate cytotoxicity with mean cell viability of 80% and 60%, respectively; while tantalum nanoparticles (TaNPs) and bismuth nanoparticles (BiNPs) did not show cytotoxicity, with cell viability of 94% and 90%, respectively. The copper (I) complex showed better efficacy in promastigotes (IC50 0.071 mM) and amastigotes [reduction of 75% of the infection rate (IR)] of L. (V.) braziliensis. Palladium (II) complexes were effective in inhibiting promastigotes (IC50 < 0.00037 mM) and in amastigote forms showed a 20% reduction in the IR of L. (L.) amazonensis and L. (V.) guyanensis. TaNPs induced parasitic inhibition of promastigote (IC50 3 μM) and amastigotes (50% reduction in IR) of L. (V.) braziliensis. BiNPs showed better efficacy in inhibiting promastigotes (IC50 0.05 μM) and amastigotes (70% reduction in the infection rate) of L. (L.) amazonensis. In vivo assays were performed with copper (I) complex and TaNPs and general data from in vivo biological assays demonstrated that topical treatment with ointment containing copper (I) complex showed low efficacy in reducing the volume of the snout of hamsters (reduction < 18%) and intralesional treatment with TaNPs induced a significant increase (increase of 28%) in mouse paw volume, with an exacerbated inflammatory action at the site of application of TaNPs. According to the obtained results, it was evident that the inorganic substances tested showed promising activity in vitro, especially in promastigote forms and with moderate or minimal cytotoxicity to murine peritoneal macrophages and human monocytes. In in vivo assays, copper (I) complex and TaNPs did not induce clinical and parasitological cure at the tested time, concentrations, and formulations.