Cisplatin, carboplatin, and oxaliplatin are the common platinum-based anticancer drugs widely used in the chemotherapeutic treatment of solid tumors in clinic. However, the comprehensive pharmacokinetics of platinum-based anticancer drugs has not been fully understood yet. This leads to many limitations for the further studies on their pharmacology and toxicology. In this study, we conduct a systemic evaluation on the pharmacokinetics of three platinum analogues at animal and cell levels, with quantification of both total platinum and intact drugs. A detailed animal study to address and compare the different pharmacokinetic behaviors of three platinum analogues has been conducted in three biological matrices: blood, plasma, and ultrafiltrate plasma. Carboplatin showed an obviously different pharmacokinetic characteristic from cisplatin and oxaliplatin. On the one hand, carboplatin has the highest proportion of Pt distribution in ultrafiltrate plasma. On the other hand, carboplatin has the highest intact drug exposure and longest intact drug elimination time in blood, plasma, and ultrafiltrate plasma, which may explain its high hematotoxicity. Additionally, the cellular and subcellular pharmacokinetics of oxaliplatin in two colon cancer HCT-116/LOVO cell lines has been elucidated for the first time. The biotransformation of intact oxaliplatin in cells was rapid with a fast elimination, however, the generated platinum-containing metabolites still exist within cells. The distribution of total platinum in the cytosol is higher than in the mitochondria, followed by the nucleus. Enrichment of platinum in mitochondria may affect the respiratory chain or energy metabolism, and further lead to cell apoptosis, which may indicate mitochondria as another potential target for efficacy and toxicity of oxaliplatin.
A simple LC-MS/MS method facilitated by salting-out assisted liquid-liquid extraction (SALLE) was applied to simultaneously investigate the pharmacokinetics of trans-resveratrol (Res) and its major glucuronide and sulfate conjugates in rat plasma. Acetonitrile-methanol (80:20, v/v) and ammonium acetate (10 mol L ) were used as extractant and salting-out reagent to locate the target analytes in the supernatant after the aqueous and organic phase stratification, then the analytes were determined via gradient elution by LC-MS/MS in negative mode in a single run. The analytical method was validated with good selectivity, acceptable accuracy (>85%) and low variation of precision (<15%). SALLE showed better extraction efficiency of target glucuronide and sulfate conjugates (>80%). The method was successfully applied to determine Res and its four conjugated metabolites in rat after Res administration (intragastric, 50 mg kg ; intravenous, 10 mg kg ). The systemic exposures to Res conjugates were much higher than those to Res (AUC , i.v., 7.43 μm h; p.o., 8.31 μm h); Res-3-O-β-d-glucuronide was the major metabolite (AUC , i.v., 66.1 μm h; p.o., 333.4 μm h). The bioavailability of Res was estimated to be ~22.4%. The reproducible SALLE method simplified the sample preparation, drastically improved the accuracy of the concomitant assay and gave full consideration of extraction recovery to each target analyte in bio-samples.
AbstractNano-silica modified phenolic resin film is prepared using different mass fractions of nano-silica by liquid composites molding (LCM). The effects of nano-silica on the rheology and curing of phenolic resin are studied by rheometer and differential scanning calorimeter (DSC). The results show that the viscosity of nano-silica modified phenolic resin decreases with the increase of temperature, and the viscosity is lowest between 70°C and 90°C. The appropriate resin film infusion (RFI) process is investigated, and the stepped curing process system is established. In addition, the microstructures of modified phenolic film and composites are tested by scanning electron microscope (SEM) and energy dispersive spectroscopy (EDS). Nano-silica can be uniformly dispersed in phenolic resin when the amount of nano-silica added is ≤ 4%. And the mechanical properties of nano-silica modified phenolic composites are tested by universal material testing machine. The optimum nano-silica mass loading for the improvement of mechanical properties is found. This work provides an effective way to prepare the modified phenolic resin film suitable for resin film infusion (RFI) processes, and it maybe become a backbone of thermal protection material in aerospace.
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