Oral Efficacy of a Diselenide Compound Loaded in Nanostructured Lipid Carriers in a Murine Model of Visceral Leishmaniasis

Abstract

Leishmaniasis urgently needs new oral treatments, as it is one of the most important neglected tropical diseases that affects people with poor resources. The drug discovery pipeline for oral administration currently discards entities with poor aqueous solubility and permeability (class IV compounds in the Biopharmaceutical Classification System, BCS) such as the diselenide 2m , a trypanothione reductase (TR) inhibitor. This work was assisted by glyceryl palmitostearate and diethylene glycol monoethyl ether-based nanostructured lipid carriers (NLC) to render 2m bioavailable and effective after its oral administration. The loading of 2m in NLC drastically enhanced its intestinal permeability and provided plasmatic levels higher than its effective concentration (IC 50 ). In L. infantum- infected BALB/c mice, 2m -NLC reduced the parasite burden in the spleen, liver, and bone marrow by at least 95% after 5 doses, demonstrating similar efficacy as intravenous Fungizone. Overall, compound 2m and its formulation merit further investigation as an oral treatment for visceral leishmaniasis.

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“…Although there are no data regarding the accumulation of these nanocarriers in the primary organs targeted by visceral leishmaniasis (e.g. liver, spleen, and bone marrow), only selenocompunds that reached plasma selenium concentrations higher than the in vitro intramacrophage IC 50 index showed significant antileishmania activity in infected animals (Etxebeste-Mitxeltorena et al, 2021). Singh et al also developed a biocompatible and stable AmpB lipid-based nanocarrier for oral administration by grafting carboxymethyl chitosan (CMC) on the surface of lipid nanoparticles (CMC-AmpB-LV) (Singh et al, 2022).…”

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“…This might be related to an insufficient amount of surfactant to cover the nanoparticles at low concentrations; therefore, their stability decreases, which results in coalescence and aggregation of the nanoparticles [43]. Also, it has been reported that Z av tends to be influenced by lipid and surfactant concentrations due to its straight relation with viscosity factor, which increases if lipid concentrations are near or above 10 %, resulting in an average size increase [44]. According to PI results, the surfactant concentration highly influences PI, which may be explained by recent reports showing that Lutrol ® F68 creates a stabilizer layer in the nanoparticle surface, leading to PI values around 0.2 [44,45].…”

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“…Similarly, NLCs were prepared for oral administration with diselenide, a Biopharmaceutics Classification System (BCS) class IV drug . To improve the bioavailability and efficacy of the drug, NLCs were prepared using glyceryl palmitostearate and diethylene glycol monoethyl ether.…”

“…Recently, Jesus and co-workers 64 have reported ursolic acid (UA)-loaded NLCs to treat V.L. The developed NLCs had a particle size of 266 nm with a spherical morphology and smooth surface.…”