Abstract
Purpose: Chronic infections of Candida albicans are characterised by the embedding of budding and entwined filamentous fungal cells into biofilms. The biofilms are refractory to many drugs and Candida biofilms are associated with ocular fungal infections. The objective was to test the activity of nanoparticulate amphotericin B (AmB) against Candida biofilms. Methods: AmB was encapsulated in the Molecular Envelope Technology (MET, N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan) nanoparticles and tested against Candida biofilms in vitro. Confocal laser scanning microscopy (CLSM) imaging of MET nanoparticles’ penetration into experimental biofilms was carried out and a MET-AmB eye drop formulation was tested for its stability. Results: MET-AmB formulations demonstrated superior activity towards C. albicans biofilms in vitro with the EC50 being ~30 times lower than AmB alone (EC50 MET-AmB = 1.176 μg mL−1, EC50 AmB alone = 29.09 μg mL−1). A similar superior activity was found for Candida glabrata biofilms, where the EC50 was ~10× lower than AmB alone (EC50 MET-AmB = 0.0253 μg mL−1, EC50 AmB alone = 0.289 μg mL−1). CLSM imaging revealed that MET nanoparticles penetrated through the C. albicans biofilm matrix and bound to fungal cells. The activity of MET-AmB was no different from the activity of AmB alone against C. albicans cells in suspension (MET-AmB MIC90 = 0.125 μg mL−1, AmB alone MIC90 = 0.250 μg mL−1). MET-AmB eye drops were stable at room temperature for at least 28 days. Conclusions: These biofilm activity findings raise the possibility that MET-loaded nanoparticles may be used to tackle Candida biofilm infections, such as refractory ocular fungal infections.
Highlights
Biofilms are formed on biotic and abiotic surfaces and are sometimes associated with the flow of fluid across a surface in the presence of the pathogen [1]
Which factors are dominant in the contribution to resistance are still the subject of debate and here we focus on the physical barrier to the fungal cells, offered by the biofilm itself
The MET-amphotericin B (AmB) nanoparticle eye drop formulation was stable for up to 4 weeks at refrigeration temperature in terms of drug content and there were slight changes in the level of AmB seen at intermediate time points, the drug content measured at 4 weeks showed exceptional stability at all storage conditions (Table 1)
Summary
Biofilms are formed on biotic and abiotic surfaces and are sometimes associated with the flow of fluid across a surface in the presence of the pathogen [1]. Candida biofilms consist of a complex architecture of an extracellular secreted polysaccharide-protein-lipid-based matrix [6], embedding different budding and filamentous morphological forms of Candida cells [7,8]. They are characterised by the expression of adhesion genes [2,9]. A few liposomal, lipid complex, and colloidal dispersionbased AmB formulations are clinically approved for parenteral administration [17], but their efficacy against Candida biofilm infections is modest [16]. We set out to evaluate the antibiofilm efficacy of MET-AmB towards C. albicans and C. glabrata biofilms
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