Exploring the potential of 7,4′-di(diethylamino)flavylium as a novel photosensitizer for topical photodynamic therapy of skin cancer

Abstract

Photodynamic therapy (PDT) is a minimally invasive therapeutic approach that has shown promising results in recent years, particularly in the dermatological clinical treatment of several pathologies, including neoplastic skin diseases. In light of the recent discovery of the photosensitizing properties of a water-soluble group of amino-based flavylium dyes, research efforts have led to the development of a novel synthetic dye with two diethylamino moieties in its structure, 7,4'-di(diethylamino)flavylium (7,4′diN(Et) 2 ). This dye was tested as a potential photosensitizer for PDT of skin cancer. A single light dose of 22.5 J/cm 2 efficiently killed SCC-25 (squamous cell carcinoma) and A375 (melanoma) cells, reducing cellular viability by more than 80% in the presence of the flavylium at 0.75 µM. Meanwhile, the negligible cellular toxicity of the dye in the absence of light stimulus points out a wide and safe therapeutic window. Interestingly, significant light-induced toxicity effects were still observed after washing out the compound before cell irradiation. Moreover, out of the three prototype flavyliumloaded hydrogels, each one based on a different polymer (Carbomer, Caesalpinia Spinosa Gum and Hydroxypropyl methyl cellulose), carbomer-based formulation stood out for its substantial absorbance and fluorescence increment and enhanced 1 O 2 photogeneration activity compared to the flavylium in aqueous solution. The findings of this study provide valuable insights concerning the potential of this flavylium dye as a candidate for photodynamic therapy of skin cancer and strongly support the need for further testing in more advanced biological settings to fully assess its efficacy and safety.The use of light in combination with chemical agents as a treatment modality can be traced back to ancient civilizations but it was not until the early 20th century that this therapy gained reinvigorated interest 1 . Since then, PDT has been progressively developing into a mature technology with well-established key principles. Those consist of the combination of three individually innocuous components that become lethal to the target tumor cells when combined: a photosensitizer (PS) that is delivered and accumulates within the target biological tissue, molecular oxygen, and an external light source with an appropriate emission bandwidth that coincides with the absorption band of the PS. The photoactivation of the PS causes an exacerbated generation of reactive oxygen species (ROS), which although essential at physiological levels, result in severe and irreversible cellular damage when present at unusually high levels, leading to cell death through apoptosis, necrosis, or autophagy 2 .The dermatological clinical application of PDT has shown remarkable results in treating several skin disorders, from acne and psoriasis to pre-and cancerous lesions such as actinic keratoses and squamous cell carcinoma, respectively 3 . In the context of skin cancer, PDT has gradually emerged as an alternative treatment, used alone or in combinatio...