Caracterização do dietilditiocarbamato de sódio como um potencial fármaco na terapêutica da doença de Chagas

Abstract

Chagas disease is an endemic zoonosis in Latin America and primarily affects poorer populations. The available drugs to treat both diseases exhibit low effectiveness against intracellular forms, high toxicity, low bioavailability, and thus compromise patient safety. Therefore, for several decades, there has been a search to assess the possibility of using other medications for this disease. One promising candidate is sodium diethyldithiocarbamate (DETC), already described as a compound highly effective against Leishmania sp. and Trypanosoma cruzi in in vitro and in vivo models. However, aiming to improve its bioavailability and reduce toxicity, this work evaluated the use of a nanosystem and the free molecule in an in vitro, in silico, and in vivo approach against Trypanosoma cruzi. The nanoparticle was formulated by nanoprecipitation using PLA as a polymer and characterized in terms of physicochemical properties, cytotoxicity, cellular penetration, and antiparasitic activity. It was observed that the nanosystem, after PLA-DETC nanoformulation based on physicochemical characteristics, proved to be stable, with an average size < 200nm, IPD <0.3, and zeta potential of -20 mV. Additionally, in the cytotoxicity evaluation, it showed low cellular toxicity, not causing a reduction greater than 20% in cell viability. Moreover, it highlighted the ability to penetrate cells in a test with 3T3 and RAW cell lines within 24 hours and also managed to inhibit nearly 70% of the Dm28c strain of T. cruzi within 24 hours. Furthermore, it induced an increase of nearly 70% in reactive oxygen species within the parasites, an important factor that can lead the parasite to death. Furthermore, an in silico approach revealed that DETC presents a more suitable ADMET profile based on physicochemical and medicinal chemical properties when compared to traditionally used drugs against Chagas disease, indicating lower toxicity. Additionally, the in vivo toxicity of both the PLA-DETC nanoparticle and the free drug at concentrations of 300mg/kg and 1000mg/kg was assessed, evaluating hematological, biochemical, histopathological, and physical parameters following the OECD-recommended acute toxicity characterization in test 423. Few alterations were observed compared to the control group, primarily a 10% reduction in platelet levels, an increase in AST levels, and a decrease in creatinine levels. Additionally, there were no significant changes in the weight of the animals, which followed the same pattern as the control group, nor were there observed behavioral changes in the animals. Finally, infection and treatment protocols were evaluated using DETC (300 mg/kg, 100 mg/kg, 0.36 mg, and 0.18 mg) and PLA-DETC nanoparticle (0.36 mg and 0.18 mg), showing statistically significant reduction for DETC at a concentration of 100 mg/kg, similar to benznidazole. Furthermore, during the 7-day treatment, few changes were promoted, resulting in low compound toxicity. Therefore, DETC has shown potential as a drug in Chagas disease therapy; however, further validations are required, particularly in the chronic phase of the disease, to provide more data on this promising compound.