Keratinophilic photosensitizers for the photodynamic therapy of onychomycosis

Reference Number TO 44-00013

Keywords

onychomycosis, nail fungus, photodynamic therapy (PDT), photosensitizer (PS), reactive oxygen species (ROS), nail penetration, keratinophilic

Invention Novelty

Onychomycosis is one of the most common nail disorders: a chronic, progressive infection that can cause pain, serves as a reservoir for recurrent tinea pedis and poses risks for diabetic patients. Oral antifungals are effective but require monitoring for hepatotoxicity and drug interactions – relevant for the elderly, multimorbid patients most often affected. Topicals are well tolerated but limited by poor nail penetration and low complete cure rates; the most effective, efinaconazole, requires once-daily application to toenails for 48 weeks. Photodynamic therapy (PDT) combines a photosensitizer (PS) with light to generate reactive oxygen species (ROS) acting on multiple, non-specific targets, so resistance is considered unlikely. Clinical results with methylene blue and 5-ALA are encouraging, but these PS absorb poorly in the nail-penetrating 500–600 nm window and rely heavily on nail pre-treatment. The present inventions provide two chemically distinct PS families designed for potent photodynamic activity, activation at 500–600 nm and keratinophilicity.

Value Proposition

Keratinophilic PS that are activated in the nail-penetrating 500–600 nm window and penetrate deeper into keratin than approved antifungal lacquers in a bovine nail model, with no detectable passage through the keratin membrane. The photodynamic effect is therefore largely confined to the keratinized compartment, limiting exposure of the surrounding tissue. The target product is a medicinal nail lacquer combined with a defined LED light source, aiming to match the efficacy of current premium topicals with a few treatment sessions instead of daily application over many months. Two structurally independent chemotypes reduce compound-specific development risk and offer potential for further keratin-associated infections.

Identification of naphthazarine photosensitizers for nail PDT. Screening in T. rubrum and C. albicans cell assays and in infected bovine hoof keratin models, combined with irradiation at keratin-penetrating wavelengths, identified a naphthazarine PS optimized for PDT of onychomycosis (from Baier et al., 2023).

Technology Description

Naphthazarines (henna-related): Modification of the naphthazarine scaffold yielded PS with PDT-IC₅₀ values of 1-32 nM against Trichophyton rubrum and in the sub-micromolar range against Candida albicans, while showing no relevant activity without irradiation (IC₅₀ > 10 µM). In a bovine hoof keratin model, semi-quantitative Raman microscopy showed penetration depths of 50–70 µm for the lead compounds, compared with about 40 µm for ciclopirox and no detectable penetration for amorolfine. In a T. rubrum-infected keratin model, PDT-treated membranes showed no visible fungal growth over 10 days (see Figure).

BODIPYs: A second, structurally unrelated family showed sub-micromolar PDT activity against T. rubrum and C. albicans, penetration depths of 60–70 µm for the lead compounds and no visible fungal growth in the infected keratin model. A color change upon irradiation visibly indicates activation and consumption of the PS.

Commercial Opportunity

Available for a joint feasibility study with an option to license.

Development Status

Preclinical; both families have been characterized in fungal cell assays and in bovine hoof keratin models. Human nail penetration, cytotoxicity and phototoxicity, as well as formulation and stability form the core of the proposed feasibility study. Larger-scale synthesis is planned to provide material for partner studies.