Enhancing Flucytosine Anticandidal Activity Using PEGylated Squalene Nanocarrier

There is an emerging necessity for improved therapies against Candida‐related infections, with significant implications for global healthcare. Current antifungal agents, limited in number, target specific pathways, but resistance remains a concern. Flucytosine (5FC) exhibits antifungal activity, particularly against Candida. However, monotherapy efficacy is limited, necessitating combination treatments. Herein, we report PEGylated squalene‐based nanocarriers for 5FC loading, aiming to enhance its monotherapy efficacy against Candida strains. The loading of 5FC within micelles was achieved using the ultrasound‐assisted solvent evaporation method. The 5FC‐loaded micelles, together with non‐loaded micelles, were thoroughly characterized and analyzed. STEM and DLS analysis confirmed the core‐shell morphology with nanometric dimensions along with improved colloidal stability. The quantification of drug loading efficiency and drug loading capacity was calculated using the UV‐Vis technique. The in vitro drug‐release studies in simulated physiological conditions showed sustained release within 48 hours. Moreover, the release kinetics calculated using mathematical models showed a Fickian diffusion drug release mechanism in simulated physiological conditions with a slower diffusion rate. The in vitro antifungal activity was tested on Candida albicans, Candida glabrata, and Candida parapsilosis. The results showed improved antifungal activity for the nanotherapeutic and unchanged in vitro toxicity toward normal cells, suggesting promising advancements in 5FC therapy. Our study focused on improving the effectiveness of the antifungal drug 5‐fluorocytosine (5FC) by loading it in micellar structures formed by PEGylated squalene copolymer. The obtained results for 5FC‐loaded micelles showed in vitro prolonged release under physiological conditions and improved in vitro antifungal activity without cytotoxicity for healthy cells in comparison with the commercial 5FC drug.