Browsing by Author "Gailer, Juergen"

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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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    Linking molecular targets of Cd in the bloodstream to organ-based adverse health effects
    (Elsevier, 2020-10-05) Hill, Alexander; Gailer, Juergen
    The chronic exposure of human populations to toxic metals remains a global public health concern. Although chronic Cd exposure is linked to kidney damage, osteoporosis and cancer, the underlying biomolecular mechanisms remain incompletely understood. Since other diseases could also be causally linked to chronic Cd exposure, a systems toxicology-based approach is needed to gain new insight into the underlying exposure-disease relationship. This approach requires one to integrate the cascade of dynamic bioinorganic chemistry events that unfold in the bloodstream after Cd enters with toxicological events that unfold in target organs over time. To this end, we have conducted a systematic literature search to identify all molecular targets of Cd in plasma and in red blood cells (RBCs). Based on this information it is impossible to describe the metabolism of Cd and the toxicological relevance of it binding to molecular targets in/on RBCs is elusive. Perhaps most importantly, the role that peptides, amino acids and inorganic ions, including HCO3-, Cl- and HSeO3- play in terms of mediating the translocation of Cd to target organs and its detoxification is poorly understood. Causally linking human exposure to this metal with diseases requires a much better integration of the bioinorganic chemistry of Cd that unfolds in the bloodstream with target organs. This from a public health point of view important goal will require collaborations between scientists from different disciplines to untangle the complex mechanisms which causally link Cd exposure to disease.
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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.
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    Toxic Metal Species and ‘Endogenous’ Metalloproteins at the Blood–Organ Interface: Analytical and Bioinorganic Aspects
    (MDPI, 2021-06-04) Bridle, Tristen; Gailer, Juergen
    Globally, human exposure to environmental pollutants causes an estimated 9 million deaths per year and it could also be implicated in the etiology of diseases that do not appear to have a genetic origin. Accordingly, there is a need to gain information about the biomolecular mechanisms that causally link exposure to inorganic environmental pollutants with distinct adverse health effects. Although the analysis of blood plasma and red blood cell (RBC) cytosol can provide important biochemical information about these mechanisms, the inherent complexity of these biological matrices can make this a difficult task. In this perspective, we will examine the use of metalloen-tities that are present in plasma and RBC cytosol as potential exposure biomarkers to assess human exposure to inorganic pollutants. Our primary objective is to explore the principal bioinorganic processes that contribute to increased or decreased metalloprotein concentrations in plasma and/or RBC cytosol. Furthermore, we will also identify metabolites which can form in the bloodstream and which contain essential as well as toxic metals for use as exposure biomarkers. While the latter metal species represent useful biomarkers for short-term exposure, endogenous plasma metal-loproteins represent indicators to assess the long-term exposure of an individual to inorganic pollutants. Based on these considerations, the quantification of metalloentities in blood plasma and/or RBC cytosol is identified as a feasible research avenue to better understand the adverse health effects that are associated with chronic exposure of various human populations to inorganic pollutants. Exposure to these pollutants will likely increase as a consequence of technological advances, including the fast-growing applications of metal-based engineering nanomaterials.