Determination of trace elements in ibuprofen drug products using microwave-assisted acid digestion and inductively coupled plasma-mass spectrometry.

Trace elements are found in most drugs as a result of the drug formulation and drug production methods. An inductively coupled plasma-mass spectrometry method for the determination of 24 trace elements (Mg, Ti, V, Cr, Mn, Cu, Fe, Co, Ni, Zn, As, Se, Mo, Ru, Rh, Pd, Ag, Cd, Sb, Ba, Ir, Pt, Au, and Pb) in solid ibuprofen tablets was established in relation to the ICH Q3D(R1) guideline, to evaluate the possibility of linking trace elemental profiles to drug formulation strategies, and to differentiate between drug products based on the trace elemental profiles. Ten European ibuprofen drug products were evaluated (n=3).

Characterization of a Threonine-Ligated Molybdenyl-Sulfide Cluster as a Putative Cyanide Poisoning Antidote; Intracellular Distribution, Effects on Organic Osmolyte Homeostasis, and Induction of Cell Death.

Binuclear molybdenum sulfur complexes are effective for the catalytic conversion of cyanide into thiocyanate. The complexes themselves exhibit low toxicity and high aqueous solubility, which render them suitable as antidotes for cyanide poisoning. The binuclear molybdenum sulfur complex [(thr)MoO(μ-S)(S)] (thr - threonine) was subjected to biological studies to evaluate its cellular accumulation and mechanism of action.

toxicological evaluation of experimental anticancer gold(i) complexes with lansoprazole-type ligands.

Gold-based compounds are of great interest in the field of medicinal chemistry as novel therapeutic (anticancer) agents due to their peculiar reactivity and mechanisms of action with respect to organic drugs. Despite their promising pharmacological properties, the possible toxic effects of gold compounds need to be carefully evaluated in order to optimize their design and applicability. This study reports on the potential toxicity of three experimental gold-based anticancer compounds featuring lansoprazole ligands () studied in an model, using rat precision cut kidney and liver slices (PCKS and PCLS, respectively).

Impact of the histone deacetylase inhibitor trichostatin A on active uptake, volume-sensitive release of taurine, and cell fate in human ovarian cancer cells.

The histone deacetylase inhibitor trichostatin A (TSA) reduces cell viability in cisplatin-sensitive (A2780WT) and cisplatin-resistant (A2780RES) human ovarian cancer cells due to progression of apoptosis (increased caspase-9 activity), autophagy (increased LC3-II expression), and cell cycle arrest (increased p21 expression). The TSA-mediated effect on p21 and caspase-9 is mainly p53 independent. Cisplatin increases DNA-damage (histone H2AX phosphorylation) in A2780WT cells, whereas cisplatin, due to reduced uptake [inductively coupled-plasma-mass spectrometry (Pt) analysis], has no DNA-damaging effect in A2780RES cells.

Distribution of platinum between nuclear and cytosolic fractions - Can subcellular fractionation be performed quantitatively?

The feasibility of quantitatively tracking platinum, derived from platinum-based compounds, during subcellular fractionation was studied. Cisplatin-exposed murine Ehrlich Lettré Ascites cells were fractionated into cytosolic and crude nuclear fractions. The latter was subsequently purified.

Laser-assisted delivery enhances topical uptake of the anticancer agent cisplatin.

Systemic chemotherapy with the anticancer agent cisplatin is approved for advanced non-melanoma skin cancer (NMSC), but topical treatment is limited by insufficient cutaneous penetration. We studied the impact of ablative fractional laser (AFL) exposure on topical cisplatin's pharmacokinetics and biodistribution in skin, using microscopic ablation zones reaching the mid- (MAZ-MD; 620 μm depth) and deep dermis (MAZ-DD; 912 μm depth) (λ = 10,600 nm, 196 MAZ/cm). Assessed in an in vitro Franz cell model after 0.

Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin.

Cisplatin occupies a crucial role in the treatment of various malignant tumors. However, its efficacy and applicability are heavily restricted by severe systemic toxicities and drug resistance. Our study exploits the active targeting of supramolecular metallacages to enhance the activity of cisplatin in cancer cells while reducing its toxicity.

Relevance of Copper and Organic Cation Transporters in the Activity and Transport Mechanisms of an Anticancer Cyclometallated Gold(III) Compound in Comparison to Cisplatin.

The molecular mechanisms of toxicity and cellular transport of anticancer metallodrugs, including platinum-based agents, have not yet been fully elucidated. The aim of our study was to investigate the relevance of copper transporters (CTR1 and ATP7A/B), organic cation transporters (OCT2) and the multidrug and toxin extrusion proteins (MATE) in the intracellular accumulation of a novel organometallic cytotoxic Au(III) compound in cancer cells in comparison to cisplatin. Specifically, the synthesis and characterization of the gold complex [Au(py-H)(PPhAr)Cl]PF (PPhAr = 3-[4-(diphenylphosphino)phenyl]-7-methoxy-2H-chromen-2-one] (), featuring a coumarin ligand endowed with "smart" fluorescence properties, have been achieved.

Development and validation of an ICP-MS method for quantification of total carbon and platinum in cell samples and comparison of open-vessel and microwave-assisted acid digestion methods.

Cisplatin is a widely used chemotherapeutic drug. Due to severe side effects and intrinsic or acquired resistance, there is a great interest in developing new platinum-based anticancer agents and a need for robust and validated analytical methods for determination of platinum accumulation in biological samples. A validated ICP-MS method for quantification of total carbon and platinum in cell samples is presented, applicable for cellular drug accumulation studies of platinum-based drugs, enabling estimation of drug accumulation while simultaneously determining carbon to monitor the sample digestion efficiency.

Cisplatin Encapsulation Generates Morphologically Different Multicompartments in the Internal Nanostructures of Nonlamellar Liquid-Crystalline Self-Assemblies.

Cisplatin ( cis-diamminedichloroplatinum(II)) is among the most potent cytotoxic agents used in cancer chemotherapy. The encapsulation of cisplatin in lipid-based drug carriers has been challenging owing to its low solubility in both aqueous and lipid phases. Here, we investigated cisplatin encapsulation in nonlamellar liquid-crystalline (LC) nanodispersions formed from a ternary mixture of phytantriol (PHYT), vitamin E (Vit E), and an anionic phospholipid [either phosphatidylglycerol (DSPG) or phosphatidylserine (DPPS)].

On the toxicity and transport mechanisms of cisplatin in kidney tissues in comparison to a gold-based cytotoxic agent.

Mechanisms of toxicity and cellular transport of anticancer metallodrugs, including platinum-based agents, have not yet been fully elucidated. Here, we studied the toxic effects and accumulation mechanisms of cisplatin in healthy rat kidneys ex vivo, using the Precision Cut Tissue Slices (PCTS) method. In addition, for the first time, we investigated the nephrotoxic effects of an experimental anticancer cyclometallated complex [Au(py-H)(PTA)Cl]PF (PTA = 1,3,5-triazaphosphaadamantane).

Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells.

Acquired resistance to chemotherapeutic drugs in cancer cells can reflect an ability to limit cellular drug availability, to repair drug induced DNA damage, and to limit initiation/progression of cell death (apoptosis). The leucine-rich-repeat-containing 8A (LRRC8A) protein is an essential component of volume sensitive channels for organic osmolytes (VSOAC) and volume regulated anion channels (VRAC), which are activated during the apoptotic process. Here we illustrate that cisplatin resistance in human ovarian cancer cells (A2780) correlates with a reduced expression of LRRC8A and copper transporter receptor 1 (CTR1), as well as a concomitant increased expression of copper-transporting P-type ATPases (ATP7A/ATP7B).

Quantification of low molecular weight selenium metabolites in human plasma after treatment with selenite in pharmacological doses by LC-ICP-MS.

The paper presents an analytical method for quantification of low molecular weight (LMW) selenium compounds in human plasma based on liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS) and post column isotope dilution-based quantification. Prior to analysis, samples were ultrafiltrated using a cut-off value of 3000 Da. The method was validated in aqueous solution as well as plasma using standards of selenomethionine (SeMet), Se-methylselenocysteine (MeSeCys), selenite, and the selenosugar Se-methylseleno-N-acetylgalactosamine (SeGal) for linearity, precision, recoveries, and limits of detection and quantitation with satisfactory results.

Cellular uptake of metallated cobalamins.

Cellular uptake of vitamin B12-cisplatin conjugates was estimated via detection of their metal constituents (Co, Pt, and Re) by inductively coupled plasma mass spectrometry (ICP-MS). Vitamin B12 (cyano-cob(iii)alamin) and aquo-cob(iii)alamin [Cbl-OH2](+), which differ in the β-axial ligands (CN(-) and H2O, respectively), were included as control samples. The results indicated that B12 derivatives delivered cisplatin to both cellular cytosol and nuclei with an efficiency of one third compared to the uptake of free cisplatin cis-[Pt(II)Cl2(NH3)2].

Modulatory effect of human plasma on the internal nanostructure and size characteristics of liquid-crystalline nanocarriers.

The inverted-type liquid-crystalline dispersions comprising cubosomes and hexosomes hold much potential for drug solubilization and site-specific targeting on intravenous administration. Limited information, however, is available on the influence of plasma components on nanostructural and morphological features of cubosome and hexosome dispersions, which may modulate their stability in the blood and their overall biological performance. Through an integrated approach involving SAXS, cryo-TEM, and nanoparticle tracking analysis (NTA) we have studied the time-dependent effect of human plasma (and the plasma complement system) on the integrity of the internal nanostructure, morphology, and fluctuation in size distribution of phytantriol (PHYT)-based nonlamellar crystalline dispersions.

In vitro characterization of a novel C,N-cyclometalated benzimidazole Ru(II) arene complex: stability, intracellular distribution and binding, effects on organic osmolyte homeostasis and induction of apoptosis.

In the present work a novel C,N-cyclometalated benzimidazole Ru(ii) arene complex (GY34) was characterized by applying an alternative, diverse approach considering both chemical and biological aspects. RP-HPLC-ICP-MS and RP-HPLC-ESI-MS analysis proved that GY34 in both RPMI-1640 cell medium and ammonium acetate buffer was transformed into several subspecies and the importance of evaluating and controlling analyte stability throughout experiments was demonstrated. Applying a novel cell fractionation protocol GY34 was found to target cell nuclei and mitochondria in Ehrlich Lettré Ascites (ELA) cells, with the intracellular distribution depending on GY34 concentration in the cell medium during incubation.

Selective analysis of human serum albumin based on SEC-ICP-MS after labelling with iophenoxic acid.

Human serum albumin (HSA) is the most abundant protein in the human plasma. HSA has several physiological roles in the human body, including storage and transport. Owing to the predominance of albumin in plasma, HSA is often involved in the protein binding of drugs.

Selenium as an alternative peptide label - comparison to fluorophore-labelled penetratin.

In the present study, the impact on peptide properties of labelling peptides with the fluorophore TAMRA or the selenium (Se) containing amino acid SeMet was evaluated. Three differently labelled variants of the cell-penetrating peptide (CPP) penetratin (Pen) were synthesized, PenM(Se), TAMRA-PenM(Se) and TAMRA-Pen. The labelled peptides were characterized in terms of hydrodynamic radius, secondary structure during peptide-membrane interaction, effect on membrane leakage induction, uptake efficiency in HeLa cells.

Quantification of pharmaceutical peptides using selenium as an elemental detection label.

The aim of the present work was to demonstrate how selenium labelling of a synthetic cell-penetrating peptide may be employed in evaluation of stability and quantitative estimation of cellular uptake by inductively coupled plasma mass spectrometry (ICP-MS). Two analogues of the cell-penetrating peptide, penetratin, were synthesized, one with selenomethionine (SeMet) added at the N-terminal of the peptide (N-PenM(Se)) and the other with the internal methionine (Met) replaced with SeMet (i-PenM(Se)). The purity of the synthesized peptides was 92% for N-PenM(Se) and 89% for i-PenM(Se) as determined by liquid chromatography (LC)-ICP-MS.

Development and validation of an ICP-OES method for quantitation of elemental impurities in tablets according to coming US pharmacopeia chapters.

May 1, 2014 the United States Pharmacopeia (USP) will implement two new chapters stating limit concentrations of elemental impurities in pharmaceuticals applying inductively coupled plasma methods. In the present work an inductively coupled plasma optical emission spectrometry (ICP-OES) method for quantitation of As, Cd, Cu, Cr, Fe, Hg, Ir, Mn, Mo, Ni, Os, Pb, Pd, Pt, Rh, Ru, V and Zn in tablets according to the new USP chapters was developed. Sample preparation was performed by microwave-assisted acid digestion using a mixture of 65% HNO3 and 37% HCl (3:1, v/v).

Environmental arsenic exposure, selenium and sputum alpha-1 antitrypsin.

Exposure to arsenic in drinking water is associated with increased respiratory disease. Alpha-1 antitrypsin (AAT) protects the lung against tissue destruction. The objective of this study was to determine whether arsenic exposure is associated with changes in airway AAT concentration and whether this relationship is modified by selenium.

Genome-wide association study of serum selenium concentrations.

Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women's Health Initiative (WHI).

Determination of platinum drug release and liposome stability in human plasma by CE-ICP-MS.

An in vitro method for simultaneous assessment of platinum release and liposome stability of liposomal formulations in human plasma is demonstrated. The development and assessment of the method was performed on a PEGylated liposomal formulation containing cisplatin. Complete separation of free cisplatin, encapsulated cisplatin and cisplatin bound to plasma components was achieved by capillary electrophoresis (CE) separation and simultaneous monitoring of phosphorous (phospholipid) and platinum (cisplatin) by inductively coupled plasma mass spectrometry (ICP-MS).

Metallomics in drug development: characterization of a liposomal cisplatin drug formulation in human plasma by CE-ICP-MS.

A capillary electrophoresis inductively coupled plasma mass spectrometry method for separation of free cisplatin from liposome-encapsulated cisplatin and protein-bound cisplatin was developed. A liposomal formulation of cisplatin based on PEGylated liposomes was used as model drug formulation. The effect of human plasma matrix on the analysis of liposome-encapsulated cisplatin and intact cisplatin was studied.

Assessing element-specific patterns of bioaccumulation across New England lakes.

Little is known about differences among trace elements in patterns of bioaccumulation in freshwater food webs. Our goal was to identify patterns in bioaccumulation of different elements that are large and consistent enough to discern despite variation across lakes. We measured methylmercury (MeHg) and trace element (As, Cd, Hg, Pb, and Zn) concentrations in food web components of seven New England lakes on 3-5 dates per lake, and contrasted patterns of bioaccumulation across lakes, metals and seasons.