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

Mikel Etxebeste-Mitxeltorena,Socorro Espuelas,Manuela Carvalheiro,José I Álvarez-Galindo,Elena González-Peñas,Esther Moreno,Juan M Irache,Daniel Plano,Carmen Sanmartín,Antonio J Almeida,Iñigo Navarro-Blasco,Alba Calvo

doi:10.1021/acsinfecdis.1c00394

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 (IC50). 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.

Highlights

Leishmaniasis urgently needs new oral treatments, as it is one of the most important neglected tropical diseases that affects people with poor resources
Is the most severe form of the disease, and it is principally caused by the species L. infantum and L. donovani
This parasite resides in host macrophages, mainly from liver, spleen, bone marrow, and lymph nodes, and it causes anemia, leukopenia, hepatosplenomegaly, hypoalbuminemia, weight loss, and death if untreated.[1 300,000] out of more than 1 million reported cases of leishmaniasis every year belong to visceral leishmaniasis (VL), which is responsible for around 40,000 deaths.[2]

Summary

Introduction

Leishmaniasis urgently needs new oral treatments, as it is one of the most important neglected tropical diseases that affects people with poor resources. Is the most severe form of the disease, and it is principally caused by the species L. infantum and L. donovani This parasite resides in host macrophages, mainly from liver, spleen, bone marrow, and lymph nodes, and it causes anemia, leukopenia, hepatosplenomegaly, hypoalbuminemia, weight loss, and death if untreated.[1 300,000] out of more than 1 million reported cases of leishmaniasis every year belong to VL, which is responsible for around 40,000 deaths.[2]. B deoxycholate, lipid formulations of amphotericin B, miltefosine, and paromomycin.[3,4] All of them have limitations in terms of toxicity, variable efficacy, price, and inconvenient treatment schedules.[5] they are parenteral drugs, with the exception of miltefosine, which is orally administered

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