Osteosarcoma Cell and Osteosarcoma Stem Cell Potent Immunogenic Bi‐Nuclear Gallium(III) Complexes

We report the synthesis, characterization, anti-osteosarcoma and anti-osteosarcoma stem cells (OSC) properties (cytotoxic and immunogenic) of a series of bi-nuclear gallium(III) complexes with tridentate Schiff base ligands and 8-hydroxyquinoline (1-4). According to monolayer cytotoxicity studies, 1-4 display micromolar potency toward bulk osteosarcoma cells and OSCs. The most effective complex in series 2 is up to 13-fold more potent toward OSCs than cisplatin and carboplatin (the only metallodrugs used in the clinic to treat osteosarcoma). Remarkably, the bi-nuclear gallium(III) complexes 1-4 are significantly more potent toward 3D-cultured sarcospheres than OSCs cultured in monolayers indicating effective penetration of the sarcosphere multicellular architecture. The bi-nuclear gallium(III) complexes 1-4 are up to 53-fold more potent toward sarcospheres than cisplatin and carboplatin. Mechanistic studies show that gallium(III) complex 2 kills osteosarcoma cells by caspase-dependent apoptosis and paraptosis, leading to the release of danger-associated molecular patterns associated with immunogenic cell death. Osteosarcoma cells and OSCs treated with gallium(III) complex 2 are effectively phagocytosed by immune cells, highlighting its immunogenic potential. As far as it is known, gallium(III) complex 2 is the first metal complex to evoke an immunogenic response toward both bulk osteosarcoma cells and OSCs.