Novel Henna-Related Naphthazarine Photosensitizers for an Effective Photodynamic Therapy of Onychomycosis.

Autor: Baier J; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24116 Kiel, Germany., Jansen B; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24116 Kiel, Germany., Wenzel-Storjohann A; GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit of Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, Am Kiel-Kanal 44, 24106 Kiel, Germany., Tasdemir D; GEOMAR Centre for Marine Biotechnology (GEOMAR-Biotech), Research Unit of Marine Natural Products Chemistry, GEOMAR Helmholtz Centre for Ocean Research Kiel, Am Kiel-Kanal 44, 24106 Kiel, Germany., Peifer C; Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24116 Kiel, Germany.
Jazyk: angličtina
Zdroj: ACS pharmacology & translational science [ACS Pharmacol Transl Sci] 2023 Nov 22; Vol. 6 (12), pp. 1958-1971. Date of Electronic Publication: 2023 Nov 22 (Print Publication: 2023).
DOI: 10.1021/acsptsci.3c00259
Abstrakt: Onychomycosis caused by, e.g., Trichophyton rubrum or Candida albicans is the most common human nail disease with a worldwide prevalence of more than 10%. The therapeutic efficacy of topical antimycotics for the treatment of onychomycosis proved to be inadequate in numerous studies on patients. The main reasons are, above all, the poor bioavailability of the active ingredients in the nail compartment, causing the requirement for extremely long application periods and correspondingly high demands on adherence by the patient. In the present study, we aimed to develop a more effective and prompt photodynamic approach for the treatment of onychomycosis. The principle of photodynamic therapy (PDT) for onychomycosis has already been investigated. However, these studies used photosensitizers such as methylene blue, which were neither optimized for their keratinophilic features nor for their bioavailability in the nail. Hence, we initiated a screening campaign using T. rubrum and C. albicans cell-based assays, infected bovine keratin models, and keratin-penetrating irradiation to identify suitable hit compounds for a PDT approach toward onychomycosis. Here, we report on the discovery of Henna/Lawson-derived keratinophilic naphthazarines that act as highly potent PDT antimycotic photosensitizers with photoresponsiveness when irradiated by light at a keratin-permeable wavelength (>500 nm, e.g., compounds 10 and 11 with PDT-IC 50 = 1 and 3 nM, respectively, against T. rubrum), hence with superior efficacy than the positive controls nystatin and clotrimazole. Notably, our photodynamic approach not only affected the actual pathogens but also prevented reinfection of keratin models within 10 days, suggesting an additional efficacy against fungal spores. Compared to established concepts, our proposed PDT approach using the novel naphthazarine photosensitizers could enable an effective, precise, and sustainable therapy option for the future treatment of onychomycosis.
Competing Interests: The authors declare no competing financial interest.
(© 2023 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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