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Bernhard K Keppler - One of the best experts on this subject based on the ideXlab platform.
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studies of kp46 and KP1019 and the hydrolysis product of KP1019 in lipiodol emulsions preparation and initial characterizations as potential theragnostic agents
Current Drug Delivery, 2018Co-Authors: Irena Pashkunovamartic, Berta Cebrian Losantos, Norbert Kandler, Bernhard K KepplerAbstract:Background: Lipiodol (iodized poppy seed oil) accumulates predominately in the tumor rather than in the liver tissue [1, 2]. Therefore, mixing anticancer drugs with Lipiodol may enhance the antitumor effect by increasing the local drug concentration. Objective: In this pilot study, we made use of Lipiodol as a potential carrier of three promising antitumor metal complexes (tris(8-quinolato)gallium(III) (KP46), tetrachlorobis(indazole)ruthenate(III) (KP1019) and the hydrolysis product of KP1019, mer,trans-[RuCl3(H2O)(Hind)2]. Method: The stability of the drugs in Lipiodol and the release profile into the aqueous phase were examined independently by three different analytical techniques (high pressure liquid chromatography, HPLC; atom absorption spectroscopy, AAS; and electron spray ionization mass spectrometry, ESI-MS). Results: The complexes were stable and remained in the Lipiodol emulsion over 3 days. In contrast to KP1019 and KP46, evaluation of Lipiodol emulsions of mer, trans-[RuCl3 (H2O) (Hind) 2] was not possible due to the insolubility of the compound in Lipiodol. KP1019 released rapidly into the aqueous phase in the first week and after 1 month it was not possible to detect the complex in the emulsion. KP46 showed a gradual release with the time resulting in the release of about 6.4 % of KP46 into the aqueous phase after 1 month of incubation. Conclusion: The initial results show that Lipiodol can be successfully employed as a carrier of anticancer Ru- or Ga-complexes. Furthermore, advantages can overcome the poor water solubility of the metal complexes, opening new perspectives for the use of Lipiodol emulsions in molecular imaging and cancer therapy as theragnostic agents.
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x ray structure analysis of indazolium trans tetrachlorobis 1h indazole ruthenate iii KP1019 bound to human serum albumin reveals two ruthenium binding sites and provides insights into the drug binding mechanism
Journal of Medicinal Chemistry, 2016Co-Authors: Aleksandar Bijelic, Bernhard K Keppler, Sarah Theiner, Annette RompelAbstract:Ruthenium(III) complexes are promising candidates for anticancer drugs, especially the clinically studied indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (NKP-1339). Several studies have emphasized the likely role of human serum proteins in the transportation and accumulation of ruthenium(III) complexes in tumors. Therefore, the interaction between KP1019 and human serum albumin was investigated by means of X-ray crystallography and inductively coupled plasma mass spectrometry (ICP-MS). The structural data unambiguously reveal the binding of two ruthenium atoms to histidine residues 146 and 242, which are both located within well-known hydrophobic binding pockets of albumin. The ruthenium centers are octahedrally coordinated by solvent molecules revealing the dissociation of both indazole ligands from the ruthenium-based drug. However, a binding mechanism is proposed indicating the importance of the indazole li...
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Biodistribution of the novel anticancer drug sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] KP-1339/IT139 in nude BALB/c mice and implications on its mode of action.
Journal of Inorganic Biochemistry, 2016Co-Authors: Anna K. Bytzek, Gunda Koellensperger, Bernhard K Keppler, Christian G HartingerAbstract:Abstract The ruthenium complex sodium trans -[tetrachloridobis(1 H -indazole)ruthenate(III)] (KP-1339/IT139) has entered clinical trials as the more soluble alternative to the indazolium compound KP1019. In order to get insight into its distribution and accumulation throughout a living organism, KP-1339/IT139 was administered intravenously in non-tumor bearing nude BALB/c mice and the Ru content in blood cells and plasma, bone, brain, colon, kidneys, liver, lung, muscle, spleen, stomach and thymus was determined at several time points. The Ru concentration in blood cells and plasma was found to increase slightly within the first hours of analysis, with the Ru concentration being 3-times higher in plasma compared to blood cells. The plasma samples were subjected to analysis by capillary zone electrophoresis (CZE) and size exclusion/anion exchange chromatography (SEC-IC) both coupled to inductively coupled plasma-mass spectrometry (ICP-MS) and a large majority of the total Ru content was found attached to mouse serum albumin (MSA), confirming similar behavior to KP1019 in an in vivo setting. Within 1 h, the peak ratio of approximately 1.2–1.5 Ru per albumin molecule was reached which declined to about 1 Ru per albumin molecule within 24 h. Beside the MSA adduct a higher molecular weight species was observed probably stemming from MSA conjugates. In addition, the tissue samples were mineralized by microwave digestion and analyzed for their Ru content. The highest Ru levels were found in colon, lung, liver, kidney and notably in the thymus. The peak Ru concentrations in these tissues were reached 1–6 h after administration and declined slowly over time.
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Aqueous chemistry and antiproliferative activity of a pyrone-based phosphoramidate Ru(arene) anticancer agent
Dalton Transactions, 2014Co-Authors: Samuel M Meier, Michael A Jakupec, Bernhard K Keppler, Maria S. Novak, Wolfgang Kandioller, Alexander Roller, Christian G HartingerAbstract:A water-stable phosphoramidate Ru(arene) metallodrug shows antiproliferative activity comparable to KP1019 in human cancer cell lines. This novel compound can cross-link the peptide backbone of cytochrome c, but features low apoptosis inducing properties.
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nanoformulation improves activity of the pre clinical anticancer ruthenium complex KP1019
Journal of Biomedical Nanotechnology, 2014Co-Authors: Petra Heffeter, Wilfried Korner, Bernhard K Keppler, Christian R Kowol, Anna Riabtseva, Y Senkiv, U Jungwith, Nataliya Mitina, T Konstantinova, I B YanchukAbstract:: Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal compounds in clinical evaluation. However, although the clinical results are promising regarding both activity and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead ruthenium compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer ruthenium compounds.
Michael A Jakupec - One of the best experts on this subject based on the ideXlab platform.
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Aqueous chemistry and antiproliferative activity of a pyrone-based phosphoramidate Ru(arene) anticancer agent
Dalton Transactions, 2014Co-Authors: Samuel M Meier, Michael A Jakupec, Bernhard K Keppler, Maria S. Novak, Wolfgang Kandioller, Alexander Roller, Christian G HartingerAbstract:A water-stable phosphoramidate Ru(arene) metallodrug shows antiproliferative activity comparable to KP1019 in human cancer cell lines. This novel compound can cross-link the peptide backbone of cytochrome c, but features low apoptosis inducing properties.
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NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application
Chemical Science, 2014Co-Authors: Robert Trondl, Petra Heffeter, Michael A Jakupec, Walter Berger, Christian R Kowol, Bernhard K KepplerAbstract:NKP-1339 is the first-in-class ruthenium-based anticancer drug in clinical development against solid cancer and has recently been studied successfully in a phase I clinical trial. Ruthenium compounds such as KP1019 (indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) and NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) have a high tumour targeting potential based (1) on their strong binding to serum proteins such as albumin and transferrin as well as (2) on their activation in the reductive tumour milieu. The redox activity of ruthenium compounds is believed to represent one major mode of action leading to disturbance of the cellular redox balance and, consequently, induction of G2/M cell cycle arrest, blockage of DNA synthesis, and induction of apoptosis via the mitochondrial pathway. Moreover, potent synergistic activities of NKP-1339 with the clinically approved tyrosine kinase inhibitor sorafenib were recently reported in vitro and in vivo. Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.
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x ray absorption near edge structure spectroscopy to resolve the in vivo chemistry of the redox active indazolium trans tetrachlorobis 1h indazole ruthenate iii KP1019
Journal of Medicinal Chemistry, 2013Co-Authors: Alfred A Hummer, Petra Heffeter, Michael A Jakupec, Bernhard K Keppler, Walter Berger, Gabriel E Buchel, Martin Filipits, David V Batchelor, Annette RompelAbstract:Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (2, KP1339) are promising redox-active anticancer drug candidates that were investigated with X-ray absorption near edge structure spectroscopy. The analysis was based on the concept of the coordination charge and ruthenium model compounds representing possible coordinations and oxidation states in vivo. 1 was investigated in citrate saline buffer (pH 3.5) and in carbonate buffer (pH 7.4) at 37 °C for different time intervals. Interaction studies on 1 with glutathione in saline buffer and apo-transferrin in carbonate buffer were undertaken, and the coordination of 1 and 2 in tumor tissues was studied too. The most likely coordinations and oxidation states of the compound under the above mentioned conditions were assigned. Microprobe X-ray fluorescence of tumor thin sections showed the strong penetration of ruthenium into the tumor tissue, with the highest conce...
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Influence of ascorbic acid on the activity of the investigational anticancer drug KP1019
JBIC Journal of Biological Inorganic Chemistry, 2011Co-Authors: Caroline Bartel, Petra Heffeter, Michael A Jakupec, Walter Berger, Alexander E. Egger, Markus Galanski, Bernhard K KepplerAbstract:Ascorbic acid has been previously discussed to have antitumor potential through its interaction with transition metal ions such as iron and copper. Furthermore, ascorbic acid may act as a reducing agent for Ru(III) compounds such as indazolium trans -[tetrachlorobis(1 H -indazole)ruthenate(III)] (KP1019), an investigational anticancer drug which is supposed to be activated by reduction, prior to binding to cellular target proteins. Therefore, we investigated the influence of ascorbic acid on the activity of this antitumor metal complex in cell culture studies. We show that co-incubation of equicytotoxic, constant amounts of KP1019 with high concentrations of ascorbic acid (50–700 μM) increases cytotoxicity of the ruthenium anticancer drug in the human colon carcinoma cell line SW480, human cervical carcinoma KB-3-1 cells, and the multidrug-resistant subline KBC-1, whereas addition of low concentrations (2.7–50 μM) has a strong chemoprotective effect in the human colon carcinoma cell line SW480, but not in multidrug-resistant KBC-1 cells. Although cellular uptake of KP1019 is not altered, ascorbic acid induce stronger interaction of the ruthenium compound with DNA both in SW480 cells and under cell-free conditions with plasmid DNA. Even if DNA interactions probably play a subordinate role in vivo given the extensive protein binding of the compound, our data exemplify that ascorbic acid enhances the reactivity of KP1019 with biomolecules. Moreover, we demonstrate that the levels of KP1019-generated reactive oxygen species are markedly decreased by co-incubation with ascorbic acid. Conclusively, our results indicate that application of high doses of ascorbic acid might increase the anticancer effects of KP1019.
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en route to osmium analogues of KP1019 synthesis structure spectroscopic properties and antiproliferative activity of trans osivcl4 hazole 2
Inorganic Chemistry, 2011Co-Authors: Gabriel E Buchel, Michael A Jakupec, Bernhard K Keppler, Iryna N Stepanenko, Michaela Hejl, Vladimir B ArionAbstract:By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human ca...
Christian G Hartinger - One of the best experts on this subject based on the ideXlab platform.
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Biodistribution of the novel anticancer drug sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] KP-1339/IT139 in nude BALB/c mice and implications on its mode of action.
Journal of Inorganic Biochemistry, 2016Co-Authors: Anna K. Bytzek, Gunda Koellensperger, Bernhard K Keppler, Christian G HartingerAbstract:Abstract The ruthenium complex sodium trans -[tetrachloridobis(1 H -indazole)ruthenate(III)] (KP-1339/IT139) has entered clinical trials as the more soluble alternative to the indazolium compound KP1019. In order to get insight into its distribution and accumulation throughout a living organism, KP-1339/IT139 was administered intravenously in non-tumor bearing nude BALB/c mice and the Ru content in blood cells and plasma, bone, brain, colon, kidneys, liver, lung, muscle, spleen, stomach and thymus was determined at several time points. The Ru concentration in blood cells and plasma was found to increase slightly within the first hours of analysis, with the Ru concentration being 3-times higher in plasma compared to blood cells. The plasma samples were subjected to analysis by capillary zone electrophoresis (CZE) and size exclusion/anion exchange chromatography (SEC-IC) both coupled to inductively coupled plasma-mass spectrometry (ICP-MS) and a large majority of the total Ru content was found attached to mouse serum albumin (MSA), confirming similar behavior to KP1019 in an in vivo setting. Within 1 h, the peak ratio of approximately 1.2–1.5 Ru per albumin molecule was reached which declined to about 1 Ru per albumin molecule within 24 h. Beside the MSA adduct a higher molecular weight species was observed probably stemming from MSA conjugates. In addition, the tissue samples were mineralized by microwave digestion and analyzed for their Ru content. The highest Ru levels were found in colon, lung, liver, kidney and notably in the thymus. The peak Ru concentrations in these tissues were reached 1–6 h after administration and declined slowly over time.
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Aqueous chemistry and antiproliferative activity of a pyrone-based phosphoramidate Ru(arene) anticancer agent
Dalton Transactions, 2014Co-Authors: Samuel M Meier, Michael A Jakupec, Bernhard K Keppler, Maria S. Novak, Wolfgang Kandioller, Alexander Roller, Christian G HartingerAbstract:A water-stable phosphoramidate Ru(arene) metallodrug shows antiproliferative activity comparable to KP1019 in human cancer cell lines. This novel compound can cross-link the peptide backbone of cytochrome c, but features low apoptosis inducing properties.
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Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies
JBIC Journal of Biological Inorganic Chemistry, 2013Co-Authors: Orsolya Dömötör, Christian G Hartinger, Bernhard K Keppler, Anna K. Bytzek, Tamás Kiss, Eva A. EnyedyAbstract:Indazolium trans -[tetrachloridobis(1 H -indazole)ruthenate(III)] (KP1019) and its Na^+ analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a noncovalent manner. To elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration–UV–vis spectrophotometry, and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind to both sites with moderately strong affinity (log K _1′ = 5.3–5.8). No preference for either binding site was found, and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event. Graphical abstract
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Ruthenium versus platinum: interactions of anticancer metallodrugs with duplex oligonucleotides characterised by electrospray ionisation mass spectrometry
JBIC Journal of Biological Inorganic Chemistry, 2010Co-Authors: Michael Groessl, Christian G Hartinger, Bernhard K Keppler, Yury O. Tsybin, Paul J DysonAbstract:The binding of the ruthenium-based anticancer drug candidates KP1019, NAMI-A and RAPTA-T towards different double-stranded oligonucleotides was probed by electrospray ionisation mass spectrometry and compared with that of the widely used platinum-based chemotherapeutics cisplatin, carboplatin and oxaliplatin. It was found that the extent of adduct formation decreased in the following order: cisplatin > oxaliplatin > NAMI-A > RAPTA-T > carboplatin > KP1019. In addition to the characterisation of the adducts formed with the DNA models, the binding sites of the metallodrugs on the oligonucleotides were elucidated employing top-down tandem mass spectrometry and were found to be similar for all the metallodrugs studied, irrespective of the sequence of the oligonucleotide. A strong preference for guanine residues was established.
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pharmacokinetics of a novel anticancer ruthenium complex KP1019 ffc14a in a phase i dose escalation study
Anti-Cancer Drugs, 2009Co-Authors: Frederike Lentz, Christian G Hartinger, Bernhard K Keppler, A Drescher, Andreas Lindauer, Magdalena Henke, R A Hilger, M E Scheulen, Christian Dittrich, Ulrich JaehdeAbstract:: A phase I and pharmacokinetic study was carried out with the new ruthenium complex indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, FFC14A). Seven patients with various types of solid tumours refractory to standard therapy were treated with escalating doses of KP1019 (25-600 mg) twice weekly for 3 weeks. No dose-limiting toxicity occurred. Ruthenium plasma concentration-time profiles after the first dose and under multiple-dose conditions were analysed using a compartmental approach. The pharmacokinetic disposition was characterised by a small volume of distribution, low clearance and long half-life. Only a small fraction of ruthenium was excreted renally. The area under the curve values increased proportionally with dose indicating linear pharmacokinetics.
Petra Heffeter - One of the best experts on this subject based on the ideXlab platform.
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nanoformulation improves activity of the pre clinical anticancer ruthenium complex KP1019
Journal of Biomedical Nanotechnology, 2014Co-Authors: Petra Heffeter, Wilfried Korner, Bernhard K Keppler, Christian R Kowol, Anna Riabtseva, Y Senkiv, U Jungwith, Nataliya Mitina, T Konstantinova, I B YanchukAbstract:: Ruthenium anticancer drugs belong to the most promising non-platinum anticancer metal compounds in clinical evaluation. However, although the clinical results are promising regarding both activity and very low adverse effects, the clinical application is currently hampered by the limited solubility and stability of the drug in aqueous solution. Here, we present a new nanoparticle formulation based on polymer-based micelles loaded with the anticancer lead ruthenium compound KP1019. Nanoprepared KP1019 was characterised by enhanced stability in aqueous solutions. Moreover, the nanoparticle formulation facilitated cellular accumulation of KP1019 (determined by ICP-MS measurements) resulting in significantly lowered IC50 values. With regard to the mode of action, increased cell cycle arrest in G2/M phase (PI-staining), DNA damage (Comet assay) as well as enhanced levels of apoptotic cell death (caspase 7 and PARP cleavage) were found in HCT116 cells treated with the new nanoformulation of KP1019. Summarizing, we present for the first time evidence that nanoformulation is a feasible strategy for improving the stability as well as activity of experimental anticancer ruthenium compounds.
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NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application
Chemical Science, 2014Co-Authors: Robert Trondl, Petra Heffeter, Michael A Jakupec, Walter Berger, Christian R Kowol, Bernhard K KepplerAbstract:NKP-1339 is the first-in-class ruthenium-based anticancer drug in clinical development against solid cancer and has recently been studied successfully in a phase I clinical trial. Ruthenium compounds such as KP1019 (indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) and NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) have a high tumour targeting potential based (1) on their strong binding to serum proteins such as albumin and transferrin as well as (2) on their activation in the reductive tumour milieu. The redox activity of ruthenium compounds is believed to represent one major mode of action leading to disturbance of the cellular redox balance and, consequently, induction of G2/M cell cycle arrest, blockage of DNA synthesis, and induction of apoptosis via the mitochondrial pathway. Moreover, potent synergistic activities of NKP-1339 with the clinically approved tyrosine kinase inhibitor sorafenib were recently reported in vitro and in vivo. Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.
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poly lactic acid nanoparticles of the lead anticancer ruthenium compound KP1019 and its surfactant mediated activation
Dalton Transactions, 2014Co-Authors: Britta Fischer, Petra Heffeter, Kushtrim Kryeziu, Lars Gille, Samuel M Meier, Walter Berger, Christian R Kowol, Bernhard K KepplerAbstract:Nanoparticle formulations offer besides the advantage of passive drug targeting also the opportunity to increase the stability of drugs. KP1019 is a lead ruthenium(III) compound which has been successfully tested in a clinical phase I trial. However, it is characterized by low stability in aqueous solution especially at physiological pH. To overcome this limitation, poly(lactic acid) (PLA) nanoparticles of KP1019 with two different surfactants (Pluronic F68 and Tween 80) were prepared by a single oil-in-water (o/w) emulsion. Cytotoxicity measurements comparing different aged Tween 80 nanoparticles revealed that the color change from brown to green was associated with an up to 20 fold increased activity compared to “free” KP1019. Further investigations suggested that this is based on the formation of enhanced intracellular reactive oxygen species levels. Additional studies revealed that the origin of the green color is a reaction between KP1019 and Tween 80. Kinetic studies of this reaction mixture using UV-Vis, ESI-MS and ESR spectroscopy indicated on the one hand a coordination of Tween 80 to KP1019, and on the other hand, the color change was found to correlate with a reduction of the Ru(III) center by the surfactant. Together, the results provide a first experimental approach to stabilize a biologically active Ru(II) species of KP1019 in aqueous solution, which probably can be also used to selectively generate this activated species in the tumor tissue via delivery of KP1019 using Tween 80 nanoparticles.
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x ray absorption near edge structure spectroscopy to resolve the in vivo chemistry of the redox active indazolium trans tetrachlorobis 1h indazole ruthenate iii KP1019
Journal of Medicinal Chemistry, 2013Co-Authors: Alfred A Hummer, Petra Heffeter, Michael A Jakupec, Bernhard K Keppler, Walter Berger, Gabriel E Buchel, Martin Filipits, David V Batchelor, Annette RompelAbstract:Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (2, KP1339) are promising redox-active anticancer drug candidates that were investigated with X-ray absorption near edge structure spectroscopy. The analysis was based on the concept of the coordination charge and ruthenium model compounds representing possible coordinations and oxidation states in vivo. 1 was investigated in citrate saline buffer (pH 3.5) and in carbonate buffer (pH 7.4) at 37 °C for different time intervals. Interaction studies on 1 with glutathione in saline buffer and apo-transferrin in carbonate buffer were undertaken, and the coordination of 1 and 2 in tumor tissues was studied too. The most likely coordinations and oxidation states of the compound under the above mentioned conditions were assigned. Microprobe X-ray fluorescence of tumor thin sections showed the strong penetration of ruthenium into the tumor tissue, with the highest conce...
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Influence of ascorbic acid on the activity of the investigational anticancer drug KP1019
JBIC Journal of Biological Inorganic Chemistry, 2011Co-Authors: Caroline Bartel, Petra Heffeter, Michael A Jakupec, Walter Berger, Alexander E. Egger, Markus Galanski, Bernhard K KepplerAbstract:Ascorbic acid has been previously discussed to have antitumor potential through its interaction with transition metal ions such as iron and copper. Furthermore, ascorbic acid may act as a reducing agent for Ru(III) compounds such as indazolium trans -[tetrachlorobis(1 H -indazole)ruthenate(III)] (KP1019), an investigational anticancer drug which is supposed to be activated by reduction, prior to binding to cellular target proteins. Therefore, we investigated the influence of ascorbic acid on the activity of this antitumor metal complex in cell culture studies. We show that co-incubation of equicytotoxic, constant amounts of KP1019 with high concentrations of ascorbic acid (50–700 μM) increases cytotoxicity of the ruthenium anticancer drug in the human colon carcinoma cell line SW480, human cervical carcinoma KB-3-1 cells, and the multidrug-resistant subline KBC-1, whereas addition of low concentrations (2.7–50 μM) has a strong chemoprotective effect in the human colon carcinoma cell line SW480, but not in multidrug-resistant KBC-1 cells. Although cellular uptake of KP1019 is not altered, ascorbic acid induce stronger interaction of the ruthenium compound with DNA both in SW480 cells and under cell-free conditions with plasmid DNA. Even if DNA interactions probably play a subordinate role in vivo given the extensive protein binding of the compound, our data exemplify that ascorbic acid enhances the reactivity of KP1019 with biomolecules. Moreover, we demonstrate that the levels of KP1019-generated reactive oxygen species are markedly decreased by co-incubation with ascorbic acid. Conclusively, our results indicate that application of high doses of ascorbic acid might increase the anticancer effects of KP1019.
Annette Rompel - One of the best experts on this subject based on the ideXlab platform.
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x ray structure analysis of indazolium trans tetrachlorobis 1h indazole ruthenate iii KP1019 bound to human serum albumin reveals two ruthenium binding sites and provides insights into the drug binding mechanism
Journal of Medicinal Chemistry, 2016Co-Authors: Aleksandar Bijelic, Bernhard K Keppler, Sarah Theiner, Annette RompelAbstract:Ruthenium(III) complexes are promising candidates for anticancer drugs, especially the clinically studied indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (NKP-1339). Several studies have emphasized the likely role of human serum proteins in the transportation and accumulation of ruthenium(III) complexes in tumors. Therefore, the interaction between KP1019 and human serum albumin was investigated by means of X-ray crystallography and inductively coupled plasma mass spectrometry (ICP-MS). The structural data unambiguously reveal the binding of two ruthenium atoms to histidine residues 146 and 242, which are both located within well-known hydrophobic binding pockets of albumin. The ruthenium centers are octahedrally coordinated by solvent molecules revealing the dissociation of both indazole ligands from the ruthenium-based drug. However, a binding mechanism is proposed indicating the importance of the indazole li...
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x ray absorption near edge structure spectroscopy to resolve the in vivo chemistry of the redox active indazolium trans tetrachlorobis 1h indazole ruthenate iii KP1019
Journal of Medicinal Chemistry, 2013Co-Authors: Alfred A Hummer, Petra Heffeter, Michael A Jakupec, Bernhard K Keppler, Walter Berger, Gabriel E Buchel, Martin Filipits, David V Batchelor, Annette RompelAbstract:Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (2, KP1339) are promising redox-active anticancer drug candidates that were investigated with X-ray absorption near edge structure spectroscopy. The analysis was based on the concept of the coordination charge and ruthenium model compounds representing possible coordinations and oxidation states in vivo. 1 was investigated in citrate saline buffer (pH 3.5) and in carbonate buffer (pH 7.4) at 37 °C for different time intervals. Interaction studies on 1 with glutathione in saline buffer and apo-transferrin in carbonate buffer were undertaken, and the coordination of 1 and 2 in tumor tissues was studied too. The most likely coordinations and oxidation states of the compound under the above mentioned conditions were assigned. Microprobe X-ray fluorescence of tumor thin sections showed the strong penetration of ruthenium into the tumor tissue, with the highest conce...
