posted on 2021-11-12, 18:43authored byMikel Etxebeste-Mitxeltorena, Esther Moreno, Manuela Carvalheiro, Alba Calvo, Iñigo Navarro-Blasco, Elena González-Peñas, José I. Álvarez-Galindo, Daniel Plano, Juan M. Irache, Antonio J. Almeida, Carmen Sanmartín, Socorro Espuelas
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.