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|Author||Caterino, Marco and Herrmann, Mona and Merlino, Antonello and Riccardi, Claudia and Montesarchio, Daniela and Mroginski, Maria A. and Musumeci, Domenica and Ruffo, Francesco and Paduano, Luigi and Hildebrandt, Peter and Kozuch, Jacek and Vergara, Alessandro|
|Abstract||The Ru-III-based prodrug AziRu efficiently binds to proteins, but the mechanism of its release is still disputed. Herein, in order to test the hypothesis of a reduction-mediated Ru release from proteins, a Raman-assisted crystallographic study on AziRu binding to a model protein (hen egg white lysozyme), in two different oxidation states, Ru-II and Ru-III, was carried out. Our results indicate Ru reduction, but the Ru release upon reduction is dependent on the reducing agent. To better understand this process, a pH-dependent, spectroelectrochemical surface-enhanced Raman scattering (SERS) study was performed also on AziRu-functionalized Au electrodes as a surrogate and simplest model system of Ru-II- and Ru-III -based drugs. This SERS study provided a pK(a) of 6.0 +/- 0.4 for aquated AziRu in the Ru-III state, which falls in the watershed range of pH values separating most cancer environments from their physiological counterparts. These experiments also indicate a dramatic shift of the redox potential E-0 by >600 mV of aquated AziRu toward more positive potentials upon acidification, suggesting a selective AziRu reduction in cancer lumen but not in healthy ones. It is expected that the nature of the ligands (e.g., pyridine vs imidazole, present in well-known Ru-III complex NAMI-A) will modulate the pK(a) and E-0, without affecting the underlying reaction mechanism.|
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