Palladium(II)-Complexed meso-Tetra(4-pyridyl)porphyrin: Photodynamic Efficacy in 3D Pancreatic Cancer Models

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies, with limited therapeutic options and a highly unfavorable prognosis, largely attributed to the presence of a desmoplastic tumor microenvironment. In this study, the photodynamic efficacy of metalloporphyrin-based photosensitizerspalladium-(II)/diphosphine-coordinated meso-tetrapyridyl porphyrins, PS1 and PS2were evaluated in both homogeneous and heterogeneous 3D models of PDAC composed of MIA PaCa-2 tumor cells and pancreatic cancer-associated fibroblasts. Photodynamic therapy was conducted using red light (λ = 635 nm) at doses ranging from 1.5 to 10 J/cm², following a 90 min of incubation period. Among the tested compounds, PS2 demonstrated superior photodynamic performance in both models, exhibiting significantly lower IC₅₀ values compared to PS1, thereby indicating enhanced phototoxicity. At a concentration of 3 μM, the IC₅₀ value for PS2 was 1.3 ± 0.1 J/cm², whereas for PS1 exhibited a markedly higher IC₅₀ of 5.7 ± 0.06 J/cm². This enhanced efficacy was attributed to sustained, dose-dependent generation of reactive oxygen species and increased cellular uptake. Notably, treatment with PS2 induced calreticulin exposure on the cell surface, indicative of immunogenic cell death. Organelle-specific analyses revealed mitochondrial hyperpolarization and decreased lysosomal fluorescence, suggesting selective subcellular accumulation and functional impairment.