Abstract
Biofilm formation is responsible for the development of chronic and recurrent Candida albicans infections. The generation of biofilms is commonly accompanied by high resistance to conventional antifungal drugs, which can increase up to 1,000-fold. Fortunately, antimicrobial photodynamic therapy (aPDT) has shown excellent potential to treat biofilm infections. However, the current most commonly used photosensitizer (PS), aminolevulinic acid (ALA), is hydrophilic, unstable, and has low permeability, leading to unsatisfactory effects on biofilm eradication. To solve these problems, more stable lipophilic PSs and more effective permeability carriers could be considered as two effective solutions. Hexyl-aminolevulinate (HAL) has good bioavailability as a PS, and we proved in a previous study that ethosomes (ES), lipid-based nanocarriers, promote percutaneous drug penetration. In our previous study, a HAL-ES system presented superior photodynamic effects compared to those of ALA or HAL alone. Therefore, here, we aim to evaluate the biological effects of HAL-ES-mediated aPDT on C. albicans biofilm. An XTT sodium salt assay showed that aPDT using 0.5% HAL decreased C. albicans biofilm activity by 69.71 ± 0.43%. Moreover, aPDT with 0.5% HAL-ES further decreased biofilm activity by 92.95 ± 0.16% and inhibited growth of 25.71 ± 1.61% within 48 h, mostly via its effect on the hyphae growth, which correlated with a three-fold increase in C. albicans plasma membrane permeabilization. Notably, HAL-ES-mediated aPDT significantly reduced the sessile minimum inhibitory concentration 50 (SMIC50) of fluconazole to <2.0 μg/ml, and the 21-day survival rate of C. albicans biofilm-infected mice increased from 6.7 to 73.3%. It also significantly reduced the drug resistance and in vivo pathogenicity of C. albicans biofilm. These results demonstrate that HAL-ES-mediated aPDT could be an effective therapy for C. albicans biofilm infections; while also serving as a particularly promising effective treatment for cutaneous or mucocutaneous candidiasis and the prevention of progression to systemic candidiasis.
Highlights
Candida albicans is a fungus naturally present in the skin and mucosa of healthy people, which can be pathogenic in case of systemic or local decline of immunity
After 24 h, 0.5% HAL-ES-mediated antimicrobial photodynamic therapy (aPDT) significantly inhibited the growth of C. albicans biofilm (42.67 ± 4.24%) compared to the control group (100.00 ± 2.25%, p < 0.001)
After 48 h, when compared to the control group (100.00 ± 4.74%), 0.5% HAL-ES-mediated aPDT still inhibited the growth of C. albicans biofilm (74.29 ± 1.61%, p < 0.01)
Summary
Candida albicans is a fungus naturally present in the skin and mucosa of healthy people, which can be pathogenic in case of systemic or local decline of immunity. Cutaneous candidiasis is a common disease affecting people of all ages, accounting for approximately 7.1% of patients with dermatosis (Penate et al, 2009). With the widespread use of antifungal drugs, drug resistance in C. albicans has become increasingly severe, especially considering azoles, such as fluconazole, while biofilm formation has been identified as the leading cause underlying C. albicans drug resistance (Holmes et al, 2012). Since approximately 80% of human infections are related to biofilm formation, reduction or even elimination of biofilm is a major challenge in the treatment of fungal infections (Römling and Balsalbre, 2012)
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