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Background: Photodynamic Therapy (PDT) is a therapeutic modality that combines the application of a photoactive compound (photosensitizer, PS) with low-power light to generate reactive oxygen species in the target tissue, resulting in cytotoxic damage and cell death, while sparing adjacent tissues. The objective of this study was to evaluate the phototoxicity of a cyanine dye with two chromophores (biscyanines, BCD) in systems with varying levels of cellular organization, and we used the Photogem® (a photosensitizer approved by the Brazilian ANVISA agency for clinical use in Photodynamic Therapy) as a positive control., Materials and Methods: The cytotoxicity of the compounds was assessed in vitro in 2D monolayers, 3D spheroid cultures, and artificial skin models. Four tumoral cell lines A375 (melanoma), HCB-541 (cutaneous squamous cell carcinoma), Vu120T and Vu147T (head and neck cancer), and two normal cell lines fibroblastic HFF-1 and keratinocyte HACAT were used in this study. Cell viability, migration, production of reactive oxygen species, expression of proteins linked to DNA damage and repair, internalization, and skin permeation of PS agents., Results: Light irradiation in the presence of the PS resulted in greater cytotoxic effects for BCD as compared to Photogem®, which was accompanied by an increase in the production of reactive oxygen species including H 2 O 2 , elevated levels of cleaved PARP, and a higher rate of phosphorylated H2AX protein. BCD demonstrated enhanced internalization and bioaccumulation in the spheroids and equivalent skin models., Conclusion: BCD, as a photosensitizer, showed higher cytotoxicity, with an increased ability to generate reactive oxygen species. This led to reduced cell viability, inhibited migration, and upregulated DNA damage-related proteins. Additionally, its enhanced cellular uptake improved skin barrier permeability, making BCD a strong candidate for in vivo Photodynamic Therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)