We report the anti‐osteosarcoma stem cell (OSC) properties of a series of gallium(III)‐polypyridyl complexes (5‐7) containing diflunisal, a non‐steroidal anti‐inflammatory drug. The most effective complex within the series, 6 (containing 3,4,7,8‐tetramethyl‐1,10‐phenanthroline), displayed similar potency towards bulk osteosarcoma cells and OSCs, in the nanomolar range. Remarkably, 6 exhibited significantly higher monolayer and sarcosphere OSC potency (up to three orders of magnitude) than clinically approved drugs used in frontline (cisplatin and doxorubicin) and secondary (etoposide, ifosfamide, and carboplatin) osteosarcoma treatments. Mechanistic studies show that 6 downregulates cyclooxygenase‐2 (COX‐2) and kills osteosarcoma cells in a COX‐2 dependent manner. Furthermore, 6 induces genomic DNA damage and caspase‐dependent apoptosis. To the best of our knowledge, 6 is the first metal complex to kill osteosarcoma cells by simultaneously inhibiting COX‐2 and damaging nuclear DNA.

The anti-breast cancer stem cell (CSC) properties of a series of gold(I) complexes comprising of various non-steroidal anti-inflammatory drugs (NSAIDs) and triphenylphosphine 1-8 are reported. The most effective gold(I)-NSAID complex...

In this study we deliver an immunogenic cell death-inducing copper(ii) complex, comprising of 4,7-diphenyl-1,10-phenanthroline and a Schiff base ligand, to breast cancer stem cells.

We report the synthesis, characterisation, and anti‐osteosarcoma properties of a gallium(III) complex (1) comprising of two 1,10‐phenanthroline ligands and salicylate, a non‐steroidal anti‐inflammatory drug. The gallium(III) complex 1 displays micromolar potency towards bulk osteosarcoma cells and osteosarcoma stem cells (OSCs). Notably, the gallium(III) complex 1 exhibits significantly higher toxicity towards OSCs grown in monolayer and three‐dimensional cultures than cisplatin, a frontline anti‐osteosarcoma drug. Nuclei isolation and immunoblotting studies show that the gallium(III) complex 1 enters osteosarcoma cell nuclei and induces DNA damage. Flow cytometry and cytotoxicity studies (in the presence of prostaglandin E2) indicate that the gallium(III) complex 1 downregulates cyclooxygenase‐2 (COX‐2) expression and kills osteosarcoma cells in a COX‐2‐dependent manner. Further, the mode of osteosarcoma cell death evoked by the gallium(III) complex 1 is characterised as caspase‐dependent apoptosis.

Here we report the encapsulation of an osteosarcoma stem cell (OSC) potent gallium(III)-diflunisal complex 1 into polymeric nanoparticles, and its delivery into osteosarcoma cells. At the optimum feed (20 %, 1 NP 20 ), nanoparticle encapsulation of 1 enhances potency towards bulk osteosarcoma cells and OSCs (cultured in monolayer and three-dimensional systems). Strikingly, the nanoparticle formulation exhibits up to 5645-fold greater potency towards OSCs than frontline anti-osteosarcoma drugs, doxorubicin and cisplatin. The nanoparticle formulation evokes a similar mechanism of action as the payload, which bodes well for future translation. Specifically, the nanoparticle formulation induces nuclear DNA damage, cyclooxygenase-2 downregulation, and caspase-dependent apoptosis. To the best of our knowledge, this is the first study to demonstrate that polymeric nanoparticles can be used to effectively deliver an OSC-active metal complex into osteosarcoma cells.