Estrogen-Functionalized Ru(II) Polypyridyl Complexes Self-Assemble into Aggregates and Exhibit Selective Phototoxicity against Breast Cancer Cells

Photodynamic therapy (PDT) constitutes a promising cancer treatment modality in which an administered photosensitizer is excited with visible light to induce the localized generation of cytotoxic reactive oxygen species (ROS) at the tumor site, thus minimizing damage to healthy tissues and avoiding the use of ionizing radiation. However, most photosensitizers lack inherent selectivity for cancer cells, leading to undesirable accumulation in healthy tissues. The readily formed triplet excited states of Ru(II) polypyridyl complexes, coupled with their kinetic inertness, make them suitable candidates as photosensitizers for PDT. Herein, we report the synthesis of a series of estrogen-functionalized Ru(II) complexes using click chemistry and investigate their photophysical properties and biological activity. Dynamic light scattering studies, supported by time-resolved luminescence studies, indicate that the complexes self-assemble into micelle-like structures under experimental conditions relevant to biological studies. Our findings reveal that two of these complexes exhibit highly selective light-induced cytotoxicity toward ER+ breast cancer cells compared to estrogen receptor-negative (ER-) cells, by a factor of up to 9.6. Overall, this study highlights the potential of estrogen-conjugated Ru(II) complexes for targeted PDT, as well as the importance of aggregation in enhancing cellular uptake.