Electrospun patches to deliver combination drug therapy for fungal infections

Abstract

Fungal infections, though affecting healthcare globally, receive insufficient attention in clinical and academic settings. Invasive fungal infections, particularly caused by combat wounds, have been identified as a critical threat by the US Department of Defense. Monotherapy with traditional antifungals is often insufficient, and so combination therapies are explored to enhance treatment efficacy. However, systemic combination treatments can result in severe adverse effects, suggesting the need for localised delivery systems, such as drug-loaded electrospun patches, to administer antifungals directly to the infection site. This proof-of-concept study hypothesised that dual amorolfine and terbinafine therapy slowly releasing from electrospun patches would be an effective way of eradicating Candida albicans when the patch was applied directly to the fungal colony. The feasibility of creating electrospun materials loaded with amorolfine and terbinafine for combination antifungal therapy was investigated. Electrospinning was used to fabricate polycaprolactone (PCL) patches with varying drug loadings (2.5%, 5%, and 10% w/w) of amorolfine and terbinafine either individually or in combination. The incorporation of both drugs in the fibres was confirmed, with the drugs predominantly in an amorphous state. Results showed that combination therapy patches had a significantly greater and prolonged antifungal effect compared to monotherapy patches, with larger zones of inhibition and sustained efficacy over at least 7 days. This study therefore demonstrates that PCL-based electrospun patches containing amorolfine and terbinafine provide superior antifungal activity against C. albicans compared to monotherapy patches. This approach could lower required drug doses, reducing adverse effects, and enhance patient compliance due to prolonged drug release, leading to more effective antifungal therapy.

Keywords: drug combination; electrospinning; fungus; infection; patch.

FIGURE 1

Scanning electron micrographs (A); and fibre diameter size distribution curves (B) for unloaded PCL fibres (blank) and combination therapy patches at different drug loadings (Mix 2.5%, 5%, and 10%). Scale bar = 80 µm.

FIGURE 2

Physicochemical characterisation. FTIR (A), XRD (B) and DSC (C) data confirm the mostly amorphous nature of amorolfine and terbinafine within the electrospun patches. The TGA analysis (D) around the boiling point of TFE (shaded in grey) showed no residual solvent present in electrospun patches.

FIGURE 3

Antifungal effect of electrospun patches presented as zone of inhibition (ZOI) of C. albicans growth in a disc diffusion test. The drug combination formulations gave a larger ZOI occurring over a longer period of time following transfer of patches to freshly fungus-inoculated agar plates, showing a more potent antifungal effect than single-drug formulations (amorolfine and terbinafine) at all tested concentrations (2.5% (A), 5% (B), 10% (C) w/w drug: polymer). Sustained drug release is evidenced by prolonged antifungal effects visible over at least 8 days. Two-way ANOVA showed a significant difference between monotherapy (either amorolfine or terbinafine) and combination therapy (Mix) for 5% and 10% drug loadings at all tested timepoints (p < 0.05). Data are presented as mean ± SD, n = 3.