Pharmacokinetics and tissue distribution of novel platinum containing anticancer agent BP-C1 studied in rabbits using sector field inductively coupled plasma mass spectrometry.
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ABSTRACT: A method of platinum quantification in whole blood samples after microwave digestion using sector field inductively coupled plasma mass spectrometry has been developed. The following analytical figures of merit have been established: limit of detection 1.1 µg/L for blood samples, dynamic range 3.6-200 µg/L, intra-day precision (relative standard deviation, n = 9) did not exceed 5%. Spiked samples were analyzed for method validation. The method was used for pharmacokinetics studies of a novel anti-cancer drug BP-С1, a complex of cis-configured platinum and benzene-poly-carboxylic acids. Main pharmacokinetic parameters (area under curve, maximum concentration, clearance, half-life times for α- and β-phase) were estimated for two dosage forms of BP-C1 0.05 and 0.125 mass %. Pharmacokinetic curves were assessed for single and course administration. Studies were performed using rabbits (n = 6) as a model. BP-C1 was injected intramuscularly. The study established dose proportionality of the tested dosage forms and suggested clinical dosing schedule: 5 days of injections followed by 2 days' break. Platinum tissue distribution was studied in tissue samples collected 20 days after the last injection. Predominant platinum accumulation was observed in kidneys, liver, and muscles near injection site. 'Slow' phase of platinum excretion kinetics may be related to the muscles at the injection site.
Project description:OBJECTIVE: To develop, validate, and apply a method for the determination of platinum contamination, originating from cisplatinum, oxaliplatinum, and carboplatinum. METHODS: Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine platinum in wipe samples. The sampling procedure and the analytical conditions were optimised and the assay was validated. The method was applied to measure surface contamination in seven Dutch hospital pharmacies. RESULTS: The developed method allowed reproducible quantification of 0.50 ng l(-1) platinum (5 pg/wipe sample). Recoveries for stainless steel and linoleum surfaces ranged between 50.4 and 81.4% for the different platinum compounds tested. Platinum contamination was reported in 88% of the wipe samples. Although a substantial variation in surface contamination of the pharmacies was noticed, in most pharmacies, the laminar-airflow (LAF) hoods, the floor in front of the LAF hoods, door handles, and handles of service hatches showed positive results. This demonstrates that contamination is spread throughout the preparation rooms. CONCLUSION: We developed and validated an ultra sensitive and reliable ICP-MS method for the determination of platinum in surface samples. Surface contamination with platinum was observed in all hospital pharmacies sampled. The interpretation of these results is, however, complicated.
Project description:We developed extraction and analysis protocols for element detection in neonatal blood spots (NBSs) using sector-field inductively coupled plasma-mass spectrometry (SF-ICP-MS). A 5% (v/v) nitric acid element extraction protocol was optimized and used to simultaneously measure 28 elements in NBS card filter paper and 150 NBSs. NBS element concentrations were corrected for filter paper background contributions estimated from measurements in samples obtained from either unspotted or spotted NBS cards. A lower 95% uncertainty limit (UL) that accounted for ICP-MS method, filter paper element concentration, and element recovery uncertainties was calculated by standard methods for each individual's NBS element concentration. Filter paper median element levels were highly variable within and between lots for most elements. After accounting for measurement uncertainties, 11 elements (Ca, Cs, Cu, Fe, K, Mg, Na, P, Rb, S, and Zn) had lower 95% ULs>0?ng/spot with estimated concentrations ranging from 0.05 to >50,000?ng/spot in ?50% of NBS samples in both correction methods. In a NBS sample minority, Li, Cd, Cs, Cr, Ni, Mo, and Pb had estimated concentrations ?20-fold higher than the respective median level. Taking measurement uncertainties into account, this assay could be used for semiquantitative newborn blood element measurement and for the detection of individuals exposed to supraphysiologic levels of some trace elements. Adequate control of filter paper element contributions remains the primary obstacle to fully quantitative element measurement in newborn blood using NBSs.
Project description:Particulate emissions from vehicle exhaust catalysts are the primary contributors to platinum group elements (PGEs) being released into roadside environments, especially platinum (Pt) particles. With increasing traffic density, it is essential to quantify the emission, accumulation, and potential health effects of traffic-emitted Pt particles. In this study, three procedures were investigated to extract Pt nanoparticles (NPs) from sediments and characterize them by single-particle inductively coupled plasma time-of-flight mass spectrometry (spICP-TOF-MS). For this purpose, a reference sediment sample was spiked with manufactured Pt NPs. Pt NPs' extraction recoveries reached from 50% up to 102%, depending on the extraction procedure and whether the particle mass or number was used as the metric. Between 17% and 35% of the Pt NPs were found as unassociated Pt NPs and between 31% and 78% as Pt NPs hetero-aggregated with other sediment particles. Multi-elemental analysis of Pt-containing NPs in the pristine sediment revealed frequently co-occurring elements such as Au, Bi, and Ir, which can be used to determine a natural background baseline. Our results demonstrated that spICP-TOF-MS elemental characterization allows for distinguishing anthropogenic Pt NPs from the natural background. In the future, this could enable the sensitive monitoring of PGE release from anthropogenic sources such as vehicle exhausts.
Project description:Accurate characterization of Pt-Pd alloy nanoparticle clusters (NCs) is crucial for understanding their synthesis using Gas-Diffusion Electrocrystallization (GDEx). In this study, we propose a comprehensive approach that integrates conventional sizing techniques-scanning electron microscopy (SEM) and dynamic light scattering (DLS)-with innovative single-particle inductively coupled plasma-sector field mass spectrometry (spICP-SFMS) to investigate Pt-Pd alloy NC formation. SEM and DLS provide insights into morphology and hydrodynamic sizes, while spICP-SFMS elucidates the particle size and distribution of Pt-Pd alloy NCs, offering rapid and orthogonal characterization. The spICP-SFMS approach presented enables detailed characterization of Pt-Pd alloy NCs, which was previously challenging due to the absence of multi-element capabilities in conventional spICP-MS systems. This innovative approach not only enhances our understanding of bimetallic nanoparticle synthesis, but also paves the way for tailoring these materials for specific applications, marking a significant advancement in the field of nanomaterial science.
Project description:Metals and metal-based compounds comprise multifarious pharmaco-active and toxicological xenobiotics. From heavy metal toxicity to chemotherapeutics, the toxicokinetics of these compounds have both historical and modern-day relevance. Zebrafish have become an attractive model organism in elucidating pharmaco- and toxicokinetics in environmental exposure and clinical translation studies. Although zebrafish studies have the benefit of being higher-throughput than rodent models, there are several significant constraints to the model. One such limitation is inherent in the waterborne dosing regimen. Water concentrations from these studies cannot be extrapolated to provide reliable internal dosages. Direct measurements of the metal-based compounds allow for a better correlation with compound-related molecular and biological responses. To overcome this limitation for metals and metal-based compounds, a technique was developed to digest zebrafish larval tissue after exposure and quantify metal concentrations within tissue samples by inductively coupled plasma mass spectrometry (ICPMS). ICPMS methods were used to determine the metal concentrations of platinum (Pt) from cisplatin and ruthenium (Ru) from several novel Ru-based chemotherapeutics in zebrafish tissue. Additionally, this protocol distinguished concentrations of Pt that were sequestered in the chorion of the larval compared with the zebrafish tissue. These results indicate that this method can be applied to quantitate the metal dose present in larval tissues. Further, this method may be adjusted to identify specific metals or metal-based compounds in a broad range of exposure and dosing studies.
Project description:The increasing use of engineered nanoparticles (ENPs) in many industries has generated significant research interest regarding their impact on the environment and human health. The major routes of ENPs to enter the human body are inhalation, skin contact, and ingestion. Following ingestion, ENPs have a long contact time in the human stomach. Hence, it is essential to know the fate of the ENPs under gastric conditions. This study aims to investigate the fate of the widely used nanoparticles Ag-NP, Au-NP, CeO2-NP, and ZnO-NP in simulated gastric fluid (SGF) under different conditions through the application of single-particle inductively coupled plasma-mass spectrometry (SP-ICP-MS). The resulting analytical methods have size detection limits for Ag-NP, Au-NP, ZnO-NP, and CeO2-NP from 15 to 35 nm, and the particle concentration detection limit is 135 particles/mL. Metal ions corresponding to the ENPs of interest were detected simultaneously with detection limits from 0.02 to 0.1 μg/L. The results showed that ZnO-NPs dissolved completely and rapidly in SGF, whereas Au-NPs and CeO2-NPs showed apparent aggregation and did not dissolve significantly. Both aggregation and dissolution were observed in Ag-NP samples following exposure to SGF. The size distributions and concentrations of ENPs were affected by the original ENP concentration, ENP size, the contact time in SGF, and temperature. This work represents a significant advancement in the understanding of ENP characteristics under gastric conditions.
Project description:The discovery of the anticancer properties of platinum derivatives by Rosenberg represents a milestone in the development of chemotherapeutic protocols for tumor treatment [...].
Project description:Cisplatin, a platinum chemotherapeutic, is one of the most commonly used chemotherapeutic agents for many solid tumors. In this work, we developed and validated an inductively coupled plasma mass spectrometry (ICP-MS) method for quantitative determination of platinum levels in rat urine, plasma, and tissue matrices including liver, brain, lungs, kidney, muscle, heart, spleen, bladder, and lymph nodes. The tissues were processed using a microwave accelerated reaction system (MARS) system prior to analysis on an Agilent 7500 ICP-MS. According to the Food and Drug Administration guidance for industry, bioanalytical validation parameters of the method, such as selectivity, accuracy, precision, recovery, and stability were evaluated in rat biological samples. Our data suggested that the method was selective for platinum without interferences caused by other presenting elements, and the lower limit of quantification was 0.5 ppb. The accuracy and precision of the method were within 15% variation and the recoveries of platinum for all tissue matrices examined were determined to be 85-115% of the theoretical values. The stability of the platinum-containing solutions, including calibration standards, stock solutions, and processed samples in rat biological matrices was investigated. Results indicated that the samples were stable after three cycles of freeze-thaw and for up to three months.
Project description: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.