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 coglycolide, PLGA) show improved drug characteristics, efficacy and reduction in toxicity. Here, C-PLGA nano particles (110 nm) were synthesized by coacervation method and loaded with FLZ, achieving similar to 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 similar to 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 mu g/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.

Automated summary

This study synthesized nano carriers composed of natural and synthetic polymers for the delivery of fluconazole. The nanoformulation exhibited pH-tuned sustained drug release and showed highly effective antifungal activity against Candida and resistant Candida strains, with minimal toxicity.