Evaluating the potential of cubosomal nanoparticles for oral delivery of amphotericin B in treating fungal infection

Abstract

The oral administration of amphotericin B (AmB) has a major drawback of poor bioavailability. The aim of this study was to investigate the potential of glyceryl monoolein (GMO) cubosomes as lipid nanocarriers to improve the oral efficacy of AmB. Antifungal efficacy was determined in vivo in rats after oral administration, to investigate its therapeutic use. The human colon adenocarcinoma cell line (Caco-2) was used in vitro to evaluate transport across a model of the intestinal barrier. In vivo antifungal results showed that AmB, loaded in GMO cubosomes, could significantly enhance oral efficacy, compared against Fungizone®, and that during a 2 day course of dosage 10 mg/kg the drug reached effective therapeutic concentrations in renal tissue for treating fungal infections. In the Caco-2 transport studies, GMO cubosomes resulted in a significantly larger amount of AmB being transported into Caco-2 cells, via both clathrin- and caveolae-mediated endocytosis, but not macropinocytosis. These results suggest that GMO cubosomes, as lipid nanovectors, could facilitate the oral delivery of AmB.

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

“…AmB-GMO and AmB-PHY cubosomal formulations were stable in simulated gastric and intestinal fluids [190][191][192] and showed increased uptake by Caco-2 cells via both clathrin-and caveolae-dependent transport mechanisms [192]. Reversible decrease in TEER measurements was observed and monolayer integrity was confirmed by actin visualization [190].…”

“…In a rat model of systemic candidiasis (C. albicans ATCC 18804), oral administration of AmB-GMO (1, 5, and 10 mg/kg thrice daily for 5 days) reduced fungal burden only in kidneys, consistent with dose-dependent response in kidney tissue. [191,192] GMO cubic phase gel Intra-articular N/A N/A GMO 55%, soybean oil 5%, hyaluronic acid 0.75%, water 15%, ethanol 10%, PG 15%, AmB 0.1% w/w. Dispersion method.…”

“…Both GMO and PHY cubosomal formulations have been evaluated for oral delivery of AmB [190][191][192]. X-ray diffraction studies of freeze-dried samples showed the presence of encapsulated AmB in the amorphous form while UV-Vis spectroscopy of the colloidal dispersions revealed the incorporation of AmB predominantly in the monomeric form [190].…”

“…Pharmacokinetic studies in rats showed a significant increase in oral bioavailability of the cubosomal formulations compared to the free drug, in the order AmB-PHY > AmB-GMO >> AmB, according to the increased stability of acid-resistant PHY in the GIT [190]. In a rat model of systemic candidiasis, oral gavage administration of the AmB cubosomal formulation resulted in reduced colony counts in the kidney, but not in the spleen, liver, and lung, suggesting preferential distribution of the drug into the kidneys [192]. This aspect raises toxicity concerns, despite no signs of nephrotoxicity according to serum creatinine and blood urea nitrogen (BUN) levels [191].…”

Investigation of thiosemicarbazide free or within chitosan nanoparticles in a murine model of vulvovaginal candidiasis

“…Nanostructured drug delivery systems have been largely employed in vivo for different applications, such as to improve the oral bioavailability of the antifungal amphotericin B [16] and the intestinal permeability of itraconazole [17], to diagnosis and prognosis of cancer [18,19], and in brain tumor therapy [20]. Mucoadhesive polymers are able to adhere to the mucosa and are potential candidates for the release of therapeutic compounds to treat vulvovaginal infections [21,22].…”