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

Abstract 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.