Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS
The development of ruthenium-based complexes for cancer treatment requires a variety of pharmacological studies, one of them being a drug’s binding kinetics to serum proteins. In this work, speciation analysis was used to study kinetics of ruthenium-based drug candidates with human serum p...
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MDPI AG
2020-03-01
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| author | Katarina Marković Radmila Milačič Stefan Marković Jerneja Kladnik Iztok Turel Janez Ščančar |
| author_facet | Katarina Marković Radmila Milačič Stefan Marković Jerneja Kladnik Iztok Turel Janez Ščančar |
| author_sort | Katarina Marković |
| collection | DOAJ |
| description | The development of ruthenium-based complexes for cancer treatment requires a variety of pharmacological studies, one of them being a drug’s binding kinetics to serum proteins. In this work, speciation analysis was used to study kinetics of ruthenium-based drug candidates with human serum proteins. Two ruthenium (Ru) complexes, namely [(η<sup>6</sup>-<i>p</i>-cymene)Ru(1-hydroxypyridine-2(1<i>H</i>)-thionato)Cl] (<b>1</b>) and [(η<sup>6</sup>-<i>p</i>-cymene)Ru(1-hydroxypyridine-2(1<i>H</i>)-thionato)pta]PF<sub>6</sub> (<b>2</b>) (where pta = 1,3,5-triaza-7-phosphaadamantane), were selected. Before a kinetics study, their stability in relevant media was confirmed by nuclear magnetic resonance (NMR). Conjoint liquid chromatography (CLC) monolithic column, assembling convective interaction media (CIM) protein G and diethylamino (DEAE) disks, was used for separation of unbound Ru species from those bound to human serum transferrin (Tf), albumin (HSA) and immunoglobulins G (IgG). Eluted proteins were monitored by UV spectrometry (278 nm), while Ru species were quantified by post-column isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS). Binding kinetics of chlorido (<b>1</b>) and pta complex (<b>2</b>) to serum proteins was followed from 5 min up to 48 h after incubation with human serum. Both Ru complexes interacted mainly with HSA. Complex (<b>1</b>) exhibited faster and more extensive interaction with HSA than complex (<b>2</b>). The equilibrium concentration for complex (<b>1</b>) was obtained 6 h after incubation, when about 70% of compound was bound to HSA, 5% was associated with IgG, whereas 25% remained unbound. In contrast, the rate of interaction of complex (<b>2</b>) with HSA was much slower and less extensive and the equilibrium concentration was obtained 24 h after incubation, when about 50% of complex (<b>2</b>) was bound to HSA and 50% remained unbound. |
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| spelling | doaj.art-cfbd6800e9f14ff89b6d68317e1f04032022-12-22T03:15:35ZengMDPI AGMolecules1420-30492020-03-01257151210.3390/molecules25071512molecules25071512Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MSKatarina Marković0Radmila Milačič1Stefan Marković2Jerneja Kladnik3Iztok Turel4Janez Ščančar5Department of Environmental Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, SloveniaDepartment of Environmental Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, SloveniaDepartment of Environmental Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, SloveniaFaculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, SloveniaFaculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, SloveniaDepartment of Environmental Sciences, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, SloveniaThe development of ruthenium-based complexes for cancer treatment requires a variety of pharmacological studies, one of them being a drug’s binding kinetics to serum proteins. In this work, speciation analysis was used to study kinetics of ruthenium-based drug candidates with human serum proteins. Two ruthenium (Ru) complexes, namely [(η<sup>6</sup>-<i>p</i>-cymene)Ru(1-hydroxypyridine-2(1<i>H</i>)-thionato)Cl] (<b>1</b>) and [(η<sup>6</sup>-<i>p</i>-cymene)Ru(1-hydroxypyridine-2(1<i>H</i>)-thionato)pta]PF<sub>6</sub> (<b>2</b>) (where pta = 1,3,5-triaza-7-phosphaadamantane), were selected. Before a kinetics study, their stability in relevant media was confirmed by nuclear magnetic resonance (NMR). Conjoint liquid chromatography (CLC) monolithic column, assembling convective interaction media (CIM) protein G and diethylamino (DEAE) disks, was used for separation of unbound Ru species from those bound to human serum transferrin (Tf), albumin (HSA) and immunoglobulins G (IgG). Eluted proteins were monitored by UV spectrometry (278 nm), while Ru species were quantified by post-column isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS). Binding kinetics of chlorido (<b>1</b>) and pta complex (<b>2</b>) to serum proteins was followed from 5 min up to 48 h after incubation with human serum. Both Ru complexes interacted mainly with HSA. Complex (<b>1</b>) exhibited faster and more extensive interaction with HSA than complex (<b>2</b>). The equilibrium concentration for complex (<b>1</b>) was obtained 6 h after incubation, when about 70% of compound was bound to HSA, 5% was associated with IgG, whereas 25% remained unbound. In contrast, the rate of interaction of complex (<b>2</b>) with HSA was much slower and less extensive and the equilibrium concentration was obtained 24 h after incubation, when about 50% of complex (<b>2</b>) was bound to HSA and 50% remained unbound.https://www.mdpi.com/1420-3049/25/7/1512<b>keywords: r</b>uthenium-based chemotherapeuticsdrug candidatespyrithionekinetics studyhuman serumspeciation analysisclc monolithic chromatographycim protein g and deae disksuv spectrometryisotope dilution inductively coupled plasma mass spectrometry |
| spellingShingle | Katarina Marković Radmila Milačič Stefan Marković Jerneja Kladnik Iztok Turel Janez Ščančar Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS Molecules <b>keywords: r</b>uthenium-based chemotherapeutics drug candidates pyrithione kinetics study human serum speciation analysis clc monolithic chromatography cim protein g and deae disks uv spectrometry isotope dilution inductively coupled plasma mass spectrometry |
| title | Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS |
| title_full | Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS |
| title_fullStr | Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS |
| title_full_unstemmed | Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS |
| title_short | Binding Kinetics of Ruthenium Pyrithione Chemotherapeutic Candidates to Human Serum Proteins Studied by HPLC-ICP-MS |
| title_sort | binding kinetics of ruthenium pyrithione chemotherapeutic candidates to human serum proteins studied by hplc icp ms |
| topic | <b>keywords: r</b>uthenium-based chemotherapeutics drug candidates pyrithione kinetics study human serum speciation analysis clc monolithic chromatography cim protein g and deae disks uv spectrometry isotope dilution inductively coupled plasma mass spectrometry |
| url | https://www.mdpi.com/1420-3049/25/7/1512 |
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