Photo-Uncaging of a Microtubule-Targeted Rigidin Analogue in Hypoxic Cancer Cells and in a Xenograft Mouse Model

• DOI: 10.1021/jacs.9b07225
• Publication Date: 2019-10-18T15:01:53Z
• Authors: Vincent H. S. van...; Vadde Ramu; Austin B. Auyeung; Nataliia Beztsinna; David Y. Leger; Lucien N. Lameijer; Stan T. Hilt; Sylvia E. Le Dévédec; Tugba Yildiz; Tania Betancourt; M. Brenton Gildner; Todd W. Hudnall; Vincent Sol; Bertrand Liagre; Alexander Kornienko; Sylvestre Bonnet
• Keywords: Thioether

Marine alkaloid rigidins are cytotoxic compounds known to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing thioether group was "caged" coordination of its photosensitive ruthenium complex. In dark, coordinated fragment prevented from inhibiting tubulin polymerization and reduced toxicity in 2D cell line monolayers, 3D lung tumor spheroids (A549), xenograft (A549) nude mice. Photochemical activation prodrug upon green light irradiation led photosubstitution ligand water, thereby releasing free capable tubulin. cells, such photorelease accompanied drastic reduction growth, not only when were grown normoxia (21% O2) but also remarkably hypoxic conditions (1% O2). vivo, low observed dose 1 mg·kg-1 compound injected intraperitoneally, 30% volume reduction, which represents first demonstration safety efficacy ruthenium-based photoactivated chemotherapy xenograft.