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Red-Light Activation of a Microtubule Polymerization Inhibitor via Amide Functionalization of the Ruthenium Photocage

Bretin, Ludovic Husiev, Yurii Ramu, Vadde Zhang, Liyan Hakkennes, Matthijs Abyar, Selda Johns, Andrew C. Le Devedec, Sylvia E. Betancourt, Tania Kornienko, Alexander Bonnet, Sylvestre

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DOI/PMID/Link: 10.1002/anie.202316425

Abstract

Photoactivated chemotherapy (PACT) is a promising cancer treatment modality that kills cancer cells via photochemical uncaging of a cytotoxic drug. Most ruthenium-based photocages used for PACT are activated with blue or green light, which penetrates sub-optimally into tumor tissues. Here, we report amide functionalization as a tool to fine-tune the toxicity and excited states of a terpyridine-based ruthenium photocage. Due to conjugation of the amide group with the terpyridine π system in the excited state, the absorption of red light (630 nm) increased 8-fold, and the photosubstitution rate rose 5-fold. In vitro, red light activation triggered inhibition of tubulin polymerization, which led to apoptotic cell death both in normoxic (21 % O2 ) and hypoxic (1 % O2 ) cancer cells. In vivo, red light irradiation of tumor-bearing mice demonstrated significant tumor volume reduction (45 %) with improved biosafety, thereby demonstrating the clinical potential of this compound. Keywords: Hypoxia; Microtubule; Photocaging; Photopharmacology; Ruthenium.
Year Published 2024
Country Netherlands
Rank Positive
Journal Angewandte Chemie
Primary Topic Whole Body
Secondary Topic Cancer
Tertiary Topic Photodynamic Therapy
Model Mouse
Wavelength (nm)
Complement/Comparison Ruthenium Photocage