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Mass spectrometric analysis of ubiquitin-platinum interactions of leading anticancer drugs: MALDI versus ESI

Hartinger, Christian G., Ang, Wee Han, Casini, Angela, Messori, Luigi, Keppler, Bernhard K. and Dyson, Paul J. 2007. Mass spectrometric analysis of ubiquitin-platinum interactions of leading anticancer drugs: MALDI versus ESI. Journal of Analytical Atomic Spectrometry 22 (8) , pp. 960-967. 10.1039/B703350H

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Abstract

The protein binding of anticancer metallodrugs is regarded as an important part in their mode of action both for delivering the active moiety into the tumor but also being responsible for deactivation and/or unwanted side effects. Characterization of protein binding and release may allow new drugs to be designed which are devoid of protein interactions or capable of binding selectively to protein targets. Herein, we report the comparison of different ionization techniques, i.e. matrix-assisted laser desorption/ionization (MALDI) and nanoelectrospray ionization mass spectrometry (nESI-MS), for the analysis of small protein–platinum anticancer drug interactions. For this purpose, cisplatin, transplatin and oxaliplatin were incubated with the model proteinubiquitin (Ub) at a molar ratio of 2 : 1 (Pt : Ub) followed by MS analysis. Cisplatin, transplatin and oxaliplatin formed mainly monoadducts with Ub, but of significantly different composition. As reported earlier, cisplatin forms mainly bifunctional Ub–[Pt(NH3)2] adducts, while with transplatin the most abundant adduct was found to be a monofunctional Ub–[Pt(NH3)2Cl] species. Oxaliplatin formed exclusively bifunctional species of the formula Ub–[Pt(chxn)] (chxn = cyclohexane-1,2-diamine). The applied analysis methods provide comparable results. However, the higher resolution of the nESI-quadrupole time-of-flight (QToF)-MS allowed unambiguous characterization of a series of mono- and bis-adducts including Ub–[Pt(NH3)2(H2O)] for both cisplatin and transplatin. Applying nESI-ion trap (IT)-MS showed the advantage of higher sensitivity than the ToF instruments, allowing the detection of bisadducts of oxaliplatin after one week of incubation. In contrast to the ESI mass spectra, MALDI showed a higher degree of fragmentation of the Ub–platinum conjugates.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: Royal Society of Chemistry
Date of Acceptance: 8 May 2007
Last Modified: 04 Jun 2017 08:30
URI: http://orca.cf.ac.uk/id/eprint/79377

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