Avaliação fotodinâmica de porfirinas de Pd(II) em modelos tumorais in vitro

Abstract

Cancer remains one of the leading causes of mortality worldwide, exhibiting high therapeutic resistance and metastatic potential, which reinforces the need for alternative and selective approaches such as Photodynamic Therapy. In this work, the photodynamic potential of four meso-tetra(4-pyridyl) porphyrins complexed with palladium(II) and diphosphine ligands (Porf@dppe, Porf@dppp, Porf@dppb, and Porf@dppf) was evaluated, including photophysical characterization, biomolecular interactions, and application in different experimental cancer models, such as human melanoma (A375), murine melanoma (B16F10), and three-dimensional (3D) models of pancreatic ductal adenocarcinoma, as well as non-tumoral keratinocytes (Hacat). Photophysical characterization revealed high triplet-state formation and singlet oxygen generation yields for the Porf@dppe, Porf@dppp, and Porf@dppb complexes (ΦT ≈ 0.72–0.93; ΦΔ ≈ 0.62–0.67), whereas Porf@dppf exhibited lower values, attributed to the presence of the ferrocene unit. Studies with bovine serum albumin indicated moderate binding constants, suggesting efficient plasma transport. In two-dimensional melanoma models, the compounds exhibited low dark cytotoxicity and high phototoxicity under blue light (λ = 415 nm), with IC50 values in the nanomolar range after irradiation. Porf@dppb stood out for its higher photodynamic selectivity, whereas Porf@dppf showed greater overall cytotoxicity, associated with sustained reactive oxygen species generation. Biological assays demonstrated morphological alterations, increased reactive oxygen species levels, and reduced clonogenicity and cell migration. In 3D pancreatic ductal adenocarcinoma models, photodynamic therapy under red light (λ = 635 nm) revealed higher efficacy of Porf@dppf compared to Porf@dppb, associated with enhanced cellular uptake, sustained reactive oxygen species generation, and induction of immunogenic cell death, as evidenced by calreticulin exposure. Taken together, these results indicate that palladium(II) metalloporphyrins are promising photosensitizers for photodynamic applications in different types of cancer.