Capillary electrophoresis hyphenated to inductively coupled plasma‐mass spectrometry: A novel approach for the analysis of anticancer metallodrugs in human serum and plasma

Abstract

Capillary electrophoresis hyphenated to inductively coupled plasma-mass spectrometry: A novel approach for the analysis of anticancer metallodrugs in human serum and plasmaThe development of metal-based chemotherapeutics lacks methods which are capable of providing early indication on the potential of new metal complexes as future anticancer drugs. Since most of these compounds are administered intravenously, serum proteins are the first available biological binding partners in the bloodstream. For platinum-based anticancer drugs the interaction with serum proteins is regarded as an important contribution to the side effects accompanying chemotherapy. In contrast, newly developed ruthenium compounds are thought to be transported into the tumor in a protein-bound form. In here, the application of CE hyphenated to inductively coupled plasma (ICP)-MS, applying Polybrene-coated capillaries, is demonstrated for studying the interaction of indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) with HSA and transferrin, which are important transport proteins. Furthermore, the applicability of the method to human serum and plasma and, more importantly, to real-world patient samples was proven. KP1019 was found to bind to a high degree to HSA both in serum, plasma and the patient samples. Only minor fractions of ruthenium were found attached to other proteins.

Maltol‐Derived Ruthenium–Cymene Complexes with Tumor Inhibiting Properties: The Impact of Ligand–Metal Bond Stability on Anticancer Activity In Vitro

“…[8][9][10] The low general toxicity of these complexes reflects a more selective activity in tumor tissue compared with platinum-based compounds, mediated by transport into the cell in the form of protein adducts and reduction in the tumor. [12][13][14][15][16] More recently, the potential of organometallic Ru ii -arene compounds as anticancer agents has been recognized. [4,7,11,17] This compound type bears an arene ligand that facilitates diffusion through the cell membrane (and thereby enhances cellular uptake).…”

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

“…After intravenous administration the complex binds to highly abundant serum proteins such as human serum albumin (HSA) and transferrin (Tf) [13][14][15]. The selective tumor targeting can be realized by the enhanced permeability and retention effect of the tumor tissue, and by the overexpression of transferrin receptors on cancer cells [16].…”

“…KP1019 is known to bind to a large degree to HSA, which is suggested to act as a ruthenium reservoir [15,21,22]. HSA is the most abundant of the blood serum proteins occurring to the extent of 0.63 mM.…”

Elucidation of the Interactions of an Anticancer Ruthenium Complex in Clinical Trials with Biomolecules Utilizing Capillary Electrophoresis Hyphenated to Inductively Coupled Plasma‐Mass Spectrometry. Short Communication

“…25% of the drug coordinated to the biomolecule within 4 h. These adducts apparently exhibit rather low stability with the amount of bound Ru decreasing to 12% after 24 h. Nevertheless, the amount of Ru -5'-dGMP adducts under conditions simulating malignant tissue were significantly elevated at any time compared to reactions at (for conditions, see [20]). Reproduced with permission from [20]. Copyright: Wiley-VCH, 2008. pH 6.0 indicating why, at least in part, KP1019 is selectively active towards tumor tissue in terms of its ability to form adducts with DNA.…”