Nanoemulsion for co-encapsulation on amphotericin B and micafungin: development and characterizations of the in vitro and in vivo Candida auris potential.

Abstract

Systemic infections caused by fungi of the genus Candida, especially the new species such as C. auris, which are highly resistant to the main drugs available to the population, have been causing a serious global public health problem, especially in the nosocomial environment. Authorities around the world remain alert to the rapid progression of disease states attributed to this species due to the scarcity of drug approaches available for treatment. Potential drugs that may be used in treatment include amphotericin B (AMB) and micafungin (MICA), for which cases of microbial resistance and side effects caused by non-selectivity have been observed. In view of this, new strategies can be explored in the area of Pharmaceutical Nanotechnology. Nanoemulsions are classified as an important drug delivery system, aiming at the therapeutic improvement, lower dose and better response, selectivity and decrease of the toxic side effects. The aim of the present work is to evaluate the in vitro and in vivo potential of nanoemulsions for co-encapsulation of AMB and MICA against C. auris. Nanoemulsions will be obtained employing sunflower oil and cholesterol as oily phase, polyoxyethylene 20 cetyl ether (Brij® 58) and soybean phosphatidylcholine as the surfactant system and PBS buffer as the aqueous phase. Characterization assays (transmission electron microscopy, determination of mean particle diameter, zeta potential, polydispersity index, in vitro release assays, encapsulation efficiency of the incorporated drugs) will be performed in order to characterize the developed nanoemulsions. Biological analyzes to evaluate inhibitory potential in vitro against C. auris (determination of activity against planktonic cells, fungicidal inhibition kinetics, inhibition of mature and forming biofilms, ergosterol-sorbitol interaction assays, combination assays and resistance development) will be performed with free and incorporated MICA and AMB as well as toxicity experiments (in vitro cytotoxicity on cell lines and in vivo alternative model of acute toxicity in Gallerea melonella) and in vivo experimental therapeutic trial (in vivo experimental trial of candidemia therapy by C. auris) will be developed. This work will emphasize the importance of searching for new formulations for use in the treatment of systemic infections caused by C. auris, providing new approaches to drugs already available in therapeutics.