A pH-tuned chitosan-PLGA nanocarrier for fluconazole delivery reduces toxicity and improves efficacy against resistant Candida

Fluconazole (FLZ) is a broad-spectrum antifungal used against Candida infections. Candida auris displays resistance to FLZ. Drug nanocarriers composed of natural (chitosan, C) or synthetic polymers (polylactide co-glycolide, PLGA) show improved drug characteristics, efficacy and reduction in toxicity. Here, C-PLGA nanoparticles (110 nm) were synthesized by coacervation method and loaded with FLZ, achieving ~8-wt% drug loading. The nanoformulation displayed pH-tuned slow sustained drug release (83 %) up to 5 d, at pH 4, while 34 % release occurred at pH 7.0. Fluorescent-tagged C-PLGA-NPs were localized on the Candida cell wall/membrane as seen by confocal microscopy. This resulted in ~1.9-fold reduced efflux of R6G dye as compared to bare drug treatment in Candida albicans and resistant C. auris. The nanoformulation showed a significant 16- and 64-fold (p < 0.0001) enhanced antifungal activity (MIC 5 and 2.5 μg/ml) against C. albicans and C. auris, respectively, as compared to FLZ. The nanoformulation showed highly effective antifungal activity in-vivo against C. albicans and C. auris. Moreover, the nephrotoxicity and hepatotoxicity was negligible. Thus, PLGA NPs-mediated fluconazole delivery can contribute to increased drug efficacy and to reduce the problem of fungal resistance.