DOI: 10.1158/1535-7163.targ-23-a027 ISSN: 1538-8514

Abstract A027: A photoactivatable microtubule-targeting rigidin prodrug

Alexander Kornienko, Sylvestre Bonnet
  • Cancer Research
  • Oncology


Analogues of marine alkaloid rigidins have been found to kill cancer cells at nanomolar concentrations by targeting the microtubule network. Here, a rigidin analogue containing a thioether group was “caged” by coordination of its thioether group to a photosensitive ruthenium polypyridyl complex. In the dark, the coordinated ruthenium fragment prevented the rigidin analogue from inhibiting tubulin polymerization and reduced its toxicity in 2D cancer cell lines monolayers, 3D lung cancer tumor spheroids (A549), and in a lung cancer tumor xenograft (A549) in nude mice. Photochemical activation of the prodrug upon green light irradiation led to the photosubstitution of the thioether ligand by water, thereby releasing the free rigidin analogue capable of inhibiting the polymerization of tubulin. In cancer cells, such photorelease was accompanied by a drastic reduction of cell growth, not only when the cells were grown in normoxia (21% O2) but also, remarkably, in hypoxic conditions (1% O2). In vivo, light activation of the compound in the tumor led to 30% tumor volume reduction, which represents the first demonstration of the efficacy of a ruthenium-based photocaged compounds in a tumor xenograft. In subsequent unpublished work, we fine-tuned the excited states in this complex by adding an amide functional group on the ruthenium cage. By doing so, a new caged complex was obtained that was activated by red light (instead of green light). We demonstrated the red light activation of this compound in solution and in vitro. This result demonstrates that functionalization of ruthenium cage with electron-withdrawing groups can radically enhance their photochemical properties, which is essential for this method development (red light penetrates better into tissues than green light).  We will present our results of in vivo testing of this caged compound activated by tumor penetrable red light, where significant tumor reduction is seen in mice xenografted with subcutaneous human uveal melanoma liver metastatic cells.

Citation Format: Alexander Kornienko, Sylvestre Bonnet. A photoactivatable microtubule-targeting rigidin prodrug [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A027.

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