Osteosarcoma Cell and Osteosarcoma Stem Cell Potent Immunogenic Bi-nuclear Gallium(III) Complexes.

We report the synthesis, characterisation, 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 towards bulk osteosarcoma cells and OSCs. The most effective complex in the series 2 is up to 13-fold more potent towards 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 towards three-dimensionally 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 towards 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 to 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 we are aware, gallium(III) complex 2 is the first metal complex to evoke an immunogenic response towards both bulk osteosarcoma cells and OSCs.