A BIOPOLYMERIC CHITOSAN-ALGINATE NANOCARRIER ENHANCES FLUCONAZOLE EFFICACY IN ANTIFUNGAL THERAPY AGAINST RESISTANT CANDIDA

Henry Kolge, Gokul Patil, Shivaprakash M. Rudramurthy, Arunloke Chakrabarti, Sachin Jadhav and Vandana Ghormade*

Fluconazole, an antifungal drug faces problems of resistance due to its extensive use. Recently, biopolymeric drug nanocarriers were reported for their favorable characteristics like improved drug efficacy, biocompatibility, reduced toxicity and sustained release. Here, chitosan-alginate nanoparticles (C-Alg-NPs, 115 nm, + 37 mV charge) were fabricated by ionic gelation and loaded with fluconazole (C-Alg-Fluc NPs) having 8 weight % drug loading. The nanoformulation displayed pH-responsive (80 %) release at pH 4 in 5 d while it was low (~ 30 %) at physiological pH 7. The nanoformulation caused 1.8-fold reduced efflux activity (an antifungal resistance mechanism) in Candida albicans and resistant Candida auris as compared to the bare drug. C-Alg-NPs tagged with Cy5.5 fluorescent dye were localized in fungal cell membrane/cell wall which contributed to reduced efflux activity of fungal pathogen. The nanoformulation displayed a significantly improved 64- and 128-fold in vitro antifungal activity (MIC90 2.5 μg/ml) against C. albicans and C. auris, respectively, as compared to fluconazole. In-vivo, C-Alg-Fluc NPs displayed high efficacy against C. albicans and C. auris infected mice and reduced toxicity as compared to the bare drug. Thus, C-Alg nanocarriers are a promising antifungal treatment and can contribute to reduction of drug resistance.