Rapid LC–MS/MS method for quantification of vinorelbine and 4‐O‐deacetylvinorelbine in human whole blood suitable to monitoring oral metronomic anticancer therapy

A rapid and sensitive LC–MS/MS method for therapeutic drug monitoring oral vinorelbine (VRL) metronomic anticancer chemotherapy has been developed and validated. Analysis of VRL and its main active metabolite 4‐O‐deacetylvinorelbine (M1) was performed in whole blood matrix. Both analytes were extracted by protein precipitation and separated on an Onyx monolith C₁₈, 50 × 2 mm column then quantified by positive electrospray ionization and multiple reaction monitoring mode. The LLOQ was 0.05 ng/mL for both VRL and M1. Linearity was up to 25ng/mL with R² ≥ 0.994. The intra‐ and inter‐assay precisions were ≤ 11.6 and ≤ 10.4% while the ranges of accuracy were [−8.7%; 10.3%] and [−10.0; 7.4%] for VRL and M1, respectively. The clinical suitability of the method has been proved by the determination of the C^Trough blood concentrations of VRL and M1 in 64 nonsmall cell lung cancer elderly patients. The analytical performance of the assay was suitable for pharmacokinetic monitoring of VRL and M1, allowing the personalization of the VRL metronomic treatments.     

Testing the reliability of non-LTE spectroscopic models for complex ions

Collisional-radiative atomic models are widely used to help diagnose experimental plasma conditions through fitting and interpreting measured spectra. Here we present the results of a code comparison in which a variety of models determined plasma temperatures and densities by finding the best fit to an experimental L-shell Kr spectrum from a well characterized, but not benchmarked, laser plasma. While variations in diagnostic strategies and qualities of fit were significant, the results generally confirmed the typically quoted uncertainties for such diagnostics of ±20% in electron temperature and factors of about two in density. The comparison also highlighted some model features important for spectroscopic diagnostics: fine structure was required to match line positions and relative intensities within each charge state and for density diagnostics based on emission from metastable states; an extensive configuration set was required to fit the wings of satellite features and to reliably diagnose the temperature through the inferred charge state distribution; and the inclusion of self-consistent opacity effects was an important factor in the quality of the fit.     

Carbophilic 3‐Component Cascades: Access to Complex Bioactive Cyclopropyl Diindolylmethanes

Naturally occurring indole‐3‐carbinol and 3,3‐diindolylmethane show bioactivity in a number of disparate disease areas, including cancer, prompting substantial synthetic analogue activity. We describe a new approach to highly functionalised derivatives that starts from allene gas and proceeds via the combination of a three‐component Pd⁰‐catalysed cascade with a one‐pot, three‐component carbophilic Pt^II cascade linked to a stereoselective acid‐catalysed Mannich–Michael reaction that generates complex cyclopropyl diindolylmethanes which show selective activity against prostate cancer cell lines.     

Exploring the Potential of Metallodrugs as Chemotherapeutics for Triple Negative Breast Cancer

This review focuses on studies of coordination and organometallic compounds as potential chemotherapeutics against triple negative breast cancer (TNBC) which has one of the poorest prognoses and worst survival rates from all breast cancer types. At present, chemotherapy is still the standard of care for TNBC since only one type of targeted therapy has been recently developed. References for metal-based compounds studied in TNBC cell lines will be listed, and those of metal-specific reviews, but a detailed overview will also be provided on compounds studied in vivo (mostly in mice models) and those compounds for which some preliminary mechanistic data was obtained (in TNBC cell lines and tumors) and/or for which bioactive ligands have been used. The main goal of this review is to highlight the most promising metal-based compounds with potential as chemotherapeutic agents in TNBC.     

The synthesis,structural characterization and biological evaluation of N‐(ferrocenylmethyl amino acid) fluorinated benzene‐carboxamide derivatives as potential anticancer agents

A series of N‐(ferrocenylmethyl amino acid) fluorinated benzene‐carboxamide derivatives 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i and 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i have been synthesized by coupling ferrocenylmethyl amine 3 with various substituted N‐(fluorobenzoyl) amino acid derivatives using the standard N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride, 1‐hydroxybenzotriazole protocol. The amino acids employed in this study were glycine and L‐alanine. All of the compounds were fully characterized using a combination of ¹H NMR, ¹³C NMR, ¹⁹F NMR, distortionless enhancement by polarization transfer (DEPT)‐135, ¹H–¹H correlation spectroscopy (COSY) and ¹H–¹³C COSY (heteronuclear multiple‐quantum correlation) spectroscopy. The compounds were biologically evaluated on the oestrogen‐positive MCF‐7 breast cancer cell line. Compounds 4g , 4i , 5h and 5i exhibited cytotoxic effects on the MCF‐7 breast cancer cell line. N‐(Ferrocenylmethyl‐L‐alanine)‐3,4,5‐trifluorobenzene‐carboxamide ( 5h ) was the most active compound, with an IC₅₀ value of 2.84 μm . Compounds 4i , 5h and 5i had lower IC₅₀ values than that found for the clinically employed anticancer drug cisplatin (IC₅₀ = 16.3 μm against MCF‐7). Guanine oxidation studies confirmed that 5h was capable of generating oxidative damage via a reactive oxygen species‐mediated mechanism. Copyright © 2013 John Wiley & Sons, Ltd.     

Antioxidant activity,lipophilicity and extractability of polyphenols from pig skin – development of analytical methods for skin permeation studies

Permeation of polyphenols through the stratum corneum barrier is a precondition for the protective action of polyphenols against oxidative skin damage. Prior to in vitro skin permeation experiments, we developed a method for the quantification of polyphenols in pig skin, including organic solvent extraction and HPLC analysis. Catechine hydrate, epigallocatechin gallate, trans‐resveratrol, quercetin, rutin and protocatechuic acid were chosen for this study as representatives of phenolics with different lipophilicity and molecular weight. The antioxidative activities of polyphenols as well as their octanol–water partition coefficients at different pH values were determined. Extraction of polyphenols from pig skin was optimized by variation of solvent composition, homogenization intensity and time, as well as partial exclusion of oxygen during extraction. The highest recovery rates could be reached by extraction with the methanol–water mixture (90:10, v/v), containing 0.2 g/L l ‐ascorbic acid, after the cryo‐milling for 4 min. Recoveries of 72% for total phenolics, 96% for quercetin and protocatechuic acid, 90% for rutin and 74% for trans‐resveratrol, were achieved. These extraction parameters will be selected for the polyphenol extraction from pig skin for further in vitro drug permeation studies. Copyright © 2013 John Wiley & Sons, Ltd.     

Evaluation of calcipotriol transdermal permeation through pig,rat and mouse skin using liquid chromatography–tandem mass spectrometry

A rapid and sensitive liquid chromatography–tandem mass spectrometric method to evaluate the permeation and retention of calcipotriol in excised samples of pig, rat and mouse skin after application of a calcipotriol ointment has been developed and validated. After sample preparation of ointment, skin homogenate and receptor medium by liquid–liquid extraction, chromatography was performed on an Extend‐C₁₈ column using isocratic elution. Detection was by electrospray ionization in the negative ion mode using multiple‐reaction monitoring of the precursor to product ion transitions of calcipotriol at m/z 411.1 → 393.5, and of lovastatin (internal standard) at m/z 403.2 → 101.2. The assay was linear in all matrices with LLOQs of 1, 0.5 and 40 ng/mL for skin homogenate, receptor medium and ointment samples respectively. In terms of the permeation profiles, it was found that calcipotriol permeated through all skins to only a limited extent over 20 h after application but was efficiently retained in all skins at a level at 20 h of between 40% (pig) and 60% (rat and mouse) of the applied dose. This indicates that calcipotriol ointment has the potential to provide sustained therapeutic benefit in the treatment of psoriasis with minimal systemic side effects. Copyright © 2013 John Wiley & Sons, Ltd.     

Infrared Responsive Choline Phosphate Lipids for Synergistic Cancer Therapy

Choline phosphate lipids have been designed and developed as new-generation zwitterionic nanocarriers with excellent biocompatibility and bioorthogonality to provide a more programmable performance for cancer therapy. However, there is a lack of spatiotemporal and reversible control for drug release at target tumor cells, which can lead to severe adverse effects to normal tissue and discounted treatment outcome. Here, light-inducible Lip-cRGDfk/ICG/Dox liposomes were developed for synergistic cancer therapy. ICG can effectively convert light energy into selective heating in a local environment upon laser irradiation, thus inducing thermal ablation of tumor cells, and further reversibly trigger the spatiotemporal release of anticancer drugs (Dox) at tumor cells due to the conformation transformation of CP lipids to synergistically kill tumor cells. That Lip-cRGDfk/ICG/Dox exhibited a significant improvement for breast cancer therapy in vitro and in vivo is also demonstrated, thus it can serve as an efficient platform to noninvasively and spatiotemporally control the activation of cytotoxicity at tumor cells for precision cancer therapy.     

Multiaxial mechanical behavior of aramid fibers and identification of skin/core structure from single fiber transverse compression testing

The transverse and longitudinal mechanical properties of aramid fibers like Kevlar? 29 (K29) fibers are strongly linked to their highly oriented structure. Mechanical characterization at the single fiber scale is challenging especially when the diameter is as small as 15 µm. Longitudinal tensile tests on single K29 fibers and single fiber transverse compression test (SFTCT) have been developed. Our approach consists of coupling morphological observations and mechanical experiments with SFTCT analysis by comparing analytical solutions and finite element modeling. New insights on the analysis of the transverse direction response are highlighted. Systematic loading/unloading compression tests enable to experimentally determine a transverse elastic limit. Taking account of the strong anisotropy of the fiber, the transverse mechanical response sheds light on a skin/core architecture. More importantly, results suggest that the skin of the fiber, typically representing a shell of one micrometer in thickness, has a transverse apparent modulus of 0.2 GPa. That is around more than fifteen times lower than the transverse modulus of 3.0 GPa in the core. By comparison, the measured longitudinal modulus is about 84 GPa. The stress distribution in the fiber is explored and the critical areas for damage initiation are discussed. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 374–384