Browsing by Author "Sarpong-Kumankomah, Sophia"

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    Application of a Novel Metallomics Tool to Probe the Fate of Metal-Based Anticancer Drugs in Blood Plasma: potential, challenges and prospects
    (Bentham, 2020-06-27) Sarpong-Kumankomah, Sophia; Gailer, Juergen
    Although metallodrugs are in use to treat a variety of human disorders and exhibit a remarkable diversity of therapeutic properties, they constitute only a tiny minority of all medicinal drugs that are currently on the market. This undesirable situation must be partially attributed to our general lack of understanding the fate of metallodrugs in the extremely ligand-rich environment of the bloodstream. The challenge of gaining insight into these bioinorganic processes can be overcome by the application of ‘metallomics tools’, which involve the analysis of a biological fluid (e.g. blood plasma) with a separation method in conjunction with multi-element specific detectors. To this end, we have developed a metallomics tool that is based on size-exclusion chromatography (SEC) hyphenated to an inductively coupled plasma atomic emission spectrometer (ICP-AES). After the successful application of SEC-ICP-AES to analyze plasma for endogenous copper, iron and zinc-metalloproteins, it was subsequently applied to probe the metabolism of a variety of metal-based anticancer drugs in plasma. The versatility of this metallomics tool is exemplified by the fact that it has provided insight into the metabolism of individual Pt-based drugs, the modulation of the metabolism of cisplatin by sulfur-containing compounds, the metabolism of two metal-based drugs that contain different metals as well as a bimetallic anticancer drug, which contained two different metals. After adding pharmacologically relevant doses of metallodrugs to plasma, the temporal analysis of aliquots by SEC-ICP-AES allows to observe metal-protein adducts, metallodrug-derived degradation products and the parent metallodrug(s). This unique capability allows to obtain comprehensive insight into the fate of metal-based drugs in plasma and can be extended to in vivo studies. Thus, the application of this metallomics tool to probe the fate of novel metal-complexes in plasma that exert the desired biological activity has the potential to advance more metal-based drugs to animal/preclinical studies to fully explore the potential that metallodrugs inherently offer.
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    Employing a Metallomics Tool to Probe Bioinorganic Processes in the Bloodstream
    (2020-04-27) Sarpong-Kumankomah, Sophia; Gailer, Jürgen G.; Thurbide, Kevin B.; Jalilehvand, Farideh; Ling, Changchun; Niyogi, Som
    In this thesis, I have applied a metallomics method that is based on size exclusion chromatography coupled on-line to an inductively coupled plasma atomic emission spectrometer (SEC-ICP-AES) to analyze biological fluids to gain insight into the bioinorganic chemistry of metals and their possible link to disease processes. The first study involved the qualitative identification of an iron-containing protein in blood plasma. One of the two major iron-containing proteins in human plasma was identified as a haptoglobin-hemoglobin (Hp-Hb) complex that is formed in plasma after red blood cells rupture. Previously identified plasma metalloproteins - transferrin, ceruloplasmin and α2-macroglobulin were also unequivocally confirmed. Since the employed metallomics method can measure the concentration of these metalloproteins in plasma, the results are important as the quantification of the Hp-Hb complex in plasma gave better insight into the lysis of red blood cells, which is of immediate health relevance. In the second study, the metallomics method was applied to investigate the potential of using plasma metalloproteins as disease biomarkers. Blood serum samples from multiple sclerosis patients (21), stroke patients (17) and healthy controls (21) were analyzed for copper, iron and zinc metalloproteins. The results revealed that the concentration of the Hp-Hb complex in serum was statistically significantly higher in stroke patients compared to the other groups, which can be rationalized by the rupturing of red blood cells during a stroke event. Since 330,000 people in Canada live with long term disability effects of stroke, my results demonstrate the usefulness of the developed analytical method to diagnose diseases. The third study involved the application of the metallomics method to gain insight into the plasma transport of an arsenic-selenium compound, [(GS)2AsSe]-, that is formed in red blood cells and is excreted in bile. The analysis of [(GS)2AsSe]- added to human plasma demonstrated that [(GS)2AsSe]- mobilized Zn from plasma proteins in a dose-dependent manner. The formation of [(GS)2AsSe]- in red blood cells and its release into plasma may perturb the metabolism of zinc therein and result in systemic toxic effects. These results are relevant because the mobilization of zinc is potentially implicated in the chronic exposure of human to AsIII, which currently affects >100 million people. Lastly, the metallomics method was employed to gain insight into the stability of a bimetallic complex that has anti-cancer activity in human blood plasma. The fact that ~70 % of Titanocref remains intact in plasma after 60 min implies that this anti-cancer drug is likely to reach cancer cells in vivo. These results exemplify that conceptually-straightforward in vitro studies can provide important insight into the degradation of a bimetallic anti-cancer drug in plasma. Metallomics studies are therefore destined to play an important role in the context of advancing more metal-based drugs to preclinical studies.
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    Sample preparation of plasma enables baseline separation of iron metalloproteins by SEC-GFAAS
    (Elsevier, 2020-05-03) Miller, Kerri; Sarpong-Kumankomah, Sophia; Egorov, Artem; Gailer, Juergen
    The analysis of human plasma for biomarkers holds promise to revolutionize disease diagnosis, but is hampered by the inherent complexity of the plasma proteome. One way to overcome this problem is to analyze plasma for a sub-proteome, such as the metalloproteome. Previous studies employing size-exclusion chromatography (SEC) coupled on-line to an inductively coupled plasma-atomic emission spectrometer (ICP-AES) have revealed that plasma contains ~12 copper, iron and zinc metalloproteins. This included the iron metalloproteins transferrin (Tf) and a recently identified haptoglobin-hemoglobin (Hp-Hb) complex, which is formed in plasma when red blood cells rupture. Since this SEC-ICP-AES method required a sample volume of 500 µL to generate diagnostically useful results, we sought to develop an alternative SEC-based hyphenated approach using a smaller SEC column (150 x 5 mm I.D.) and a graphite furnace atomic absorption spectrometer (GFAAS) as the iron-specific detector. A designed interface enabled the integration of the SEC system with the GFAAS. Baseline separation between the Hp-Hb complex and Tf was achieved by developing a sample preparation procedure which involved the chelating agent-based mobilization of Fe from Tf to a small molecular weight Fe complex. Spiking of human plasma (1.0 mL) with red blood cell lysate (1-2 µL) increased only the intensity of the Fe peak corresponding to the Hp-Hb complex, but not that of Tf. Since the developed SEC-GFAAS method requires only 50 µL for analysis, it can now be employed for the cost-effective quantification of the clinically relevant Hb-Hp complex in human plasma in <50 min.
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    SEC hyphenated to a multielement-specific detector unravels the degradation pathway of a bimetallic anticancer complex in human plasma
    (Elsevier, 2020-05-15) Sarpong-Kumankomah, Sophia; Contel, Maria; Gailer, Juergen
    The bimetallic metal complex Titanocref exhibits relevant anticancer activity, but it is unknown if it is stable to reach target tissues intact. To gain insight, a pharmacologically relevant dose was added to human blood plasma and the mixture was incubated at 37ºC. The obtained mixture was analyzed 5 and 60 min later by size-exclusion chromatography hyphenated to an inductively coupled plasma atomic emission spectrometer (SEC-ICP-AES). We simultaneously detected several titanium (Ti), gold (Au) and sulfur (S)-peaks, which corresponded to a Ti degradation product that eluted partially, and a Au degradation product that eluted entirely bound to plasma proteins (both time points). Although ~70% of the intact Titanocref was retained on the column after 60 min, our results allowed us to establish ̶ for the first time ̶ its likely degradation pathway in human plasma at near physiological conditions. These results suggest that ~70% of Titanocref remain in plasma after 60 min, which supports results from a recent in vivo study in which mice were treated with Titanocref and revealed Ti:Au molar ratios in tumors and organs close to 1:1. Thus, our stability studies suggest that the intact drug is able to reach target tissue. Overall, our results exemplify that SEC-ICP-AES enables the execution of intermediate in vitro studies with human plasma in the context of advancing bimetallic metal-based drugs to more costly clinical studies.