One‐ and Two‐Photon Phototherapeutic Effects of RuII Polypyridine Complexes in the Hypoxic Centre of Large Multicellular Tumor Spheroids and Tumor‐Bearing Mice

• Published in: Chemistry : a European journal 2021-01, Vol.27 (1), p.362-370
• Main Authors: Karges, Johannes, Kuang, Shi, Ong, Yih Ching, Chao, Hui, Gasser, Gilles
• Format: Article
• Language: English
• Subjects: Alveoli; bioinorganic chemistry; Chemistry; Coordination compounds; Hypoxia; Irradiation; Lead compounds; Light irradiation; medicinal inorganic chemistry; Metal complexes; metals in medicine; Multicellular tumor spheroids; Oxygen; Photodynamic therapy; Photons; photosensitizers; Phototoxicity; Radiation; Singlet oxygen; Spheroids; Toxicity; Tumors
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202003486

During the last decades, photodynamic therapy (PDT), an approved medical technique, has received increasing attention to treat certain types of cancer. Despite recent improvements, the treatment of large tumors remains a major clinical challenge due to the low ability of the photosensitizer (PS) to penetrate a 3D cellular architecture and the low oxygen concentrations present in the tumor center. To mimic the conditions found in clinical tumors, exceptionally large 3D multicellular tumor spheroids (MCTSs) with a diameter of 800 μm were used in this work to test a series of new RuII polypyridine complexes as one‐photon and two‐photon PSs. These metal complexes were found to fully penetrate the 3D cellular architecture and to generate singlet oxygen in the hypoxic center upon light irradiation. While having no observed dark toxicity, the lead compound of this study showed an impressive phototoxicity upon clinically relevant one‐photon (595 nm) or two‐photon (800 nm) excitation with a full eradication of the hypoxic center of the MCTSs. Importantly, this efficacy was also demonstrated on mice bearing an adenocarcinomic human alveolar basal epithelial tumor. The treatment of large cancer tumors with photodynamic therapy (PDT) remains a major medical challenge due to the problems of the photosensitizers (PSs) to penetrate a 3D cellular structure and the low oxygen concentrations available in the tumor center. Herein, a series of RuII polypyridine complexes is presented as PSs for one‐ and two‐photon PDT for the treatment of the hypoxic center of exceptionally large multicellular tumor spheroids.