Banca de DEFESA: MARINA FAILLACE DE AMORIM

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : MARINA FAILLACE DE AMORIM
DATE: 16/12/2021
TIME: 09:00
LOCAL: IGM Sala Virtual 4
TITLE:

Development of the Formulation containing the Drug 17- DMAG Impregnated In Bacterial Cellulose Membrane To

Compose Scheme Therapeutic Against Cutaneous Leishmaniasis

KEY WORDS:

Leismaniasis, topical treatment, 17-DMAG, HSP90,

PAGES: 145
BIG AREA: Ciências Biológicas
AREA: Biologia Geral
SUMMARY:

ABSTRACT Leishmaniasis is a neglected tropical disease. This zooanthroponosis is endemic in more than 90 countries and in Brazil it is present in all regions, being considered a public health problem. Clinical manifestations vary between cutaneous forms that, although it is not fatal, it cause social stigma, and visceral forms, which, in turn, can be fatal. Its transmission occurs through the bite of sandflies that, during the blood meal, inoculate Leishmania promastigotes present in their saliva. The promastigotes then infect host cells and differentiate into the amastigote form. The most used current treatments are pentavalent antimonials, in addition to Amphotericin B, pentamidine, paramomycin and miltefosine, however, limitations such as side effects, invasive application, long treatment cycles, therapeutic failure or high-cost that lead to treatment abandonment. These limitations reinforce the need for the development of new leishmanicidal drugs. In this scenario, Hsp90 is a chaperone involved in the stabilization and activation process of several client proteins and important for the maintenance of cellular homeostasis. In previous studies, we demonstrated that Hsp90 inhibitors are effective in controlling infection caused by Leishmania spp. in in vitro and in vivo models, reaching zero parasite load and reducing pro-inflammatory cytokines in BALB/c mice. However, prolonged use in vivo causes toxicity. Thus, we decided to develop a less invasive, topical base formulation, that we hypothesized being able to reduce toxic effects, easy to apply, in addition to presenting cost savings. For this, we developed formulations containing 17- DMAG impregnated in bacterial cellulose membranes (BCM), which is a biopolymer with curative properties. Thus, the principal aim of this study was to evaluate the chemotherapeutic potential of 17-DMAG, an Hsp90 inhibitor, impregnated in MCB in the treatment of cutaneous leishmaniasis (CL) in in vivo and in vitro models of infection by Leishmania braziliensis. For establishing 17-DMAG impregnation of MCB, the following steps were proceed: mainly membranes were cut with a diameter of 3.5 cm, impregnated with different concentrations of 17 DMAG diluted in 5% trehalose and dried in a lyophilizer. For use in toxicitity and efficacy effects, such MCBs were cut with a 3 mm biopsy punch for in vitro assays and 8 mm for in vivo assays. We evaluated the toxicity of MCB on BMMΦ (CC50) and the efficacy against L. braziliensis axenic promastigotes (IC50). After 72 hours of treatment, we obtained a CC50 value of 30.76 ± 1.29 nM, and an IC50 of 159.9 ± 49.6 nM. Due to the IC50 value being lower than the CC50, we were unable to calculate the selectivity index. Concentration range used to determine the IC50 did not cause toxicity to macrophages, however had no effect on intracellular amastigotes. In in vivo trials at concentrations of 311 and 155 µg/cm2 showed local toxicity at two weeks of treatment, but no systemic histological alterations. The treatment using lower concentrations, between 1,000 and 125 ng/cm2 did not dissipate local toxicity, being viable for in vivo toxicity assays. These data, added to previous results with the free drug, demonstrating that, after dose adjustments, 17-DMAG impregnated in BCM will have a potential to compose a therapeutic regimen against CL.

BANKING MEMBERS:
Externa à Instituição - BEATRIZ FERREIRA DE CARVALHO PATRICIO - UNIRIO
Externo à Instituição - FABIO ROCHA FORMIGA
Presidente - 466.269.055-20 - PATRICIA SAMPAIO TAVARES VERAS - Fiocruz - RJ