PEGylated isothiocyanate-functionalized zinc(II) phthalocyanine exhibits cell-type dependent photodynamic activity in 2D and 3D tumor models

This study reports the synthesis and characterization of an asymmetric zinc(II) phthalocyanine (5) containing three tetraethyleneglycol monomethyl ether groups and one isothiocyanatophenoxy group at its periphery. The isothiocyanate unit was selected to ensure selective bioconjugation under mild reaction conditions and to reduce side product formation, while tetraethyleneglycol monomethyl ether groups were incorporated to increase solubility and tailor photophysical and photochemical properties relevant to photodynamic therapy applications. The compound showed a singlet oxygen quantum yield (Φ_Δ) of 0.38, confirming efficient photosensitizer performance. Photodynamic activity was evaluated across multiple cancer cell lines in both 2D monolayer and 3D spheroid cultures. In 2D models, compound 5 produced pronounced light-dependent cytotoxicity accompanied by increased intracellular ROS. Cell-death profiles varied among cancer types, with FaDu cells showing the highest sensitivity under the tested conditions, consistent with differences in cellular susceptibility to compound 5–mediated PDT. In 3D spheroids, efficacy was reduced, in line with known limitations of PDT in compact tumor-like structures, including restricted light propagation, oxygen gradients, and limited compound penetration. Minimal phototoxicity in non-malignant fibroblasts under the same conditions suggests preferential photodynamic activity in the tested cancer models. Overall, these results support the PDT potential of compound 5 and highlight the influence of cellular context and 3D architecture on treatment responses.