Thermosensitive system formed by poloxamers containing carvacrol: An effective carrier system against Leishmania amazonensis

Abstract

The drugs used in the treatment of leishmaniasis show problems concerning side effects and toxicity. As a result, the search for new actives is necessary, and natural products like carvacrol - 5-isopropyl-2-methylphenol, become a relevant alternative. To enable the use of carvacrol as an antileishmanial agent, thermosensitive hydrogels were developed from poloxamer triblock copolymers 407 (P407) and 188 (P188). Carvacrol-free and carvacrol-containing hydrogels were obtained from P407 alone and from the mixture of P407 and P188. The hydrogels were subjected to Differential scanning calorimetry, Small-angle X-ray scattering, Scanning electron microscopy, and Rheology analysis. The activity of hydrogels and carvacrol isolated against promastigotes and intracellular amastigotes of Leishmania amazonensis and their cytotoxicity in mammalian cells was determined. The sol-gel transition temperature for the binary hydrogel containing carvacrol (HG407/188CA) was 37.04 ± 1.35 °C. HG407/188CA presented lamellar structure at temperatures of 25 °C and 37 °C. HG407/188CA and carvacrol presented IC₅₀ against Leishmania amazonensis promastigotes of 18.68 ± 1.43 µg/mL and 23.83 ± 3.32 µg/mL, respectively, and IC₅₀ against Leishmania amazonensis amastigotes of 35.08 ± 0.75 µg/mL and 29.32 ± 0.21 µg/mL, respectively. HG407/188CA reduced the toxicity of carvacrol in all mammalian cells evaluated, raising the CC₅₀ in murine peritoneal macrophages from 40.23 ± 0.21 µg/mL to 332.6 ± 4.89 µg/mL, obtaining a Selectivity Index (SI) of 9.5 against 1.37 of the isolated carvacrol. HG407/188CA provided higher selectivity of carvacrol for the parasite. Thus, the binary hydrogel obtained may enable the use of carvacrol as a potential antileishmanial agent.

Keywords: Cytotoxicity; Drug delivery system; Hydrogel; Leishmaniasis; Monoterpene; Polymer.