A salophen cobalt(II) complex enables water oxidation at neutral pH in photoactivated sacrificial cycles under visible light, thus confirming the high appeal of earth abundant single site catalysis for artificial photosynthesis.Inspired by the natural Mn 4 CaO x oxygen evolving centre in photosystem II, 1 remarkable efforts have been dedicated towards the development of multinuclear transition metal complexes enabling water oxidation for artificial photosynthesis. 2,3 Multimetallic catalysts could in principle distribute the oxidation equivalents necessary for water oxidation over several metal centres, thus lowering the energy barrier of the overall catalytic process. 3 However, the design of multi-metallic cores with oxygen evolving activity poses synthetic and stability hurdles. Noteworthily, single site metal complexes have been recently discovered, whose oxygen evolving activity offers a major opportunity to broaden the catalyst space within fundamental coordination chemistry. 4 Of particular interest are the earth-abundant cobalt complexes featuring polydentate organic ligands, such as corroles, polypyridines, porphyrins, and polyamines, which have been used under dark electrocatalysis conditions, 5 and in few cases also within photoactivated cycles. 6 Ligand diversity is expected to play a crucial role in tuning photocatalytic water oxidation, with the urgent quest to both optimize sequential photoinduced electron transfer and facilitate the dark-phase of the catalytic mechanism under a turnover regime.In this communication we present a cobalt(II) complex with a salophen ligand (N,N 0 -bis(salicylaldehyde)-1,2-phenylenediamine), ) as the sacrificial electron acceptor (Scheme 1). Combined UV-vis, dynamic light scattering (DLS) and Electron Paramagnetic Resonance (EPR) evidence identifies CoSlp as a competent oxygen evolving catalyst (OEC), enabling a two-fold photoinduced electron transfer in the ms time-frame. Our results confirm the ''privileged'' nature of the salophen ligand environment, readily available from simple condensation reactions, with wide applicability in different fields of catalysis, including bioinspired oxidations. CoSlp is obtained by direct reaction of cobalt acetate with the salophen ligand in methanol, followed by precipitation with diethyl ether and recrystallization.8 † Its solid state and solution identity was initially verified using FT-IR and UV-vis spectroscopy through comparison with literature data (Fig. S2 and S3, ESI †), 8 then confirmed using ESI-MS, where a base peak at m/z = 374 was observed, ascribed to the [CoSlpÁH] + ion (Fig. S4, ESI †). In the solid state, the cobalt ion in CoSlp displays a square planar geometry, 8c while in aqueous solution it extends the coordination sphere to square pyramidal, by ligation of a water molecule in the apical position. 8d Spectrophotometric titration yields a pK a = 6.40 for the aquo ligand (Fig. S5, ESI †), 9 which is therefore expected to be deprotonated at neutral pH, turning into a hydroxo moiety. Characterisation of CoSlp by...

Among the several delivery materials available so far, polysaccharides represent very attractive molecules as they can undergo a wide range of chemical modifications, are biocompatible, biodegradable, and have low immunogenic properties. Thus, polysaccharides can contribute to significantly overcome the limitation in the use of many types of drugs, including anti-cancer drugs. The use of conventional anti-cancer drugs is hampered by their high toxicity, mostly depending on the indiscriminate targeting of both cancer and normal cells. Additionally, for nucleic acid based drugs (NABDs), an emerging class of drugs with potential anti-cancer value, the practical use is problematic. This mostly depends on their fast degradation in biological fluids and the difficulties to cross cell membranes. Thus, for both classes of drugs, the development of optimal delivery materials is crucial. Here we discuss the possibility of using different kinds of polysaccharides, such as chitosan, hyaluronic acid, dextran, and pullulan, as smart drug delivery materials. We first describe the main features of polysaccharides, then a general overview about the aspects ruling drug release mechanisms and the pharmacokinetic are reported. Finally, notable examples of polysaccharide-based delivery of conventional anti-cancer drugs and NABDs are reported. Whereas additional research is required, the promising results obtained so far, fully justify further efforts, both in terms of economic support and investigations in the field of polysaccharides as drug delivery materials.

Irinotecan is currently used in several cancer regimens mainly in colorectal cancer (CRC). This drug has a narrow therapeutic range and treatment can lead to side effects, mainly neutropenia and diarrhea, frequently requiring discontinuing or lowering the drug dose. A wide inter-individual variability in irinotecan pharmacokinetic parameters and pharmacodynamics has been reported and associated to patients’ genetic background. In particular, a polymorphism in the UGT1A1 gene (UGT1A1*28) has been linked to an impaired detoxification of SN-38 (irinotecan active metabolite) to SN-38 glucuronide (SN-38G) leading to increased toxicities. Therefore, therapeutic drug monitoring of irinotecan, SN-38 and SN-38G is recommended to personalize therapy. In order to quantify simultaneously irinotecan and its main metabolites in patients’ plasma, we developed and validated a new, sensitive and specific HPLC–MS/MS method applicable to all irinotecan dosages used in clinic. This method required a small plasma volume, addition of camptothecin as internal standard and simple protein precipitation. Chromatographic separation was done on a Gemini C18 column (3 μM, 100 mm x 2.0 mm) using 0.1% acetic acid/bidistilled water and 0.1% acetic acid/acetonitrile as mobile phases. The mass spectrometer worked with electrospray ionization in positive ion mode and selected reaction monitoring. The standard curves were linear (R2 ≥0.9962) over the concentration ranges (10–10000 ng/mL for irinotecan, 1–500 ng/mL for SN-38 and SN-38G and 1–5000 ng/mL for APC) and had good back-calculated accuracy and precision. The intra- and inter-day precision and accuracy, determined on three quality control levels for all the analytes, were always <12.3% and between 89.4% and 113.0%, respectively. Moreover, we evaluated this bioanalytical method by re-analysis of incurred samples as an additional measure of assay reproducibility. This method was successfully applied to a pharmacokinetic study in metastatic CRC patients enrolled in a genotype-guided phase Ib study of irinotecan administered in combination with 5-fluorouracil/leucovorin and bevacizumab.

confers a higher risk of toxicity in patients treated with irinotecan. Patients with and genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with and genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics. Previously untreated patients with mCRC (25 ; 23) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m The MTD was the highest dose at which <4/10 patients had a dose-limiting toxicity (DLT). Pharmacokinetics of irinotecan and SN-38 were measured on days 1 to 3 (without bevacizumab) and 15 to 17 (with bevacizumab). For patients, 2 DLTs were observed among 10 patients at 310 mg/m, while 370 mg/m was not tolerated (2 DLTs in 4 patients). For patients, 2 DLTs were observed among 10 patients at 260 mg/m, while 310 mg/m was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal. The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m for patients and 260 mg/m for patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab..

A novel LC-MS/MS method was developed for the quantification of the new cyclin dependent kinase inhibitors (CDKIs) palbociclib and ribociclib and the aromatase inhibitor letrozole used in combinatory regimen. The proposed method is appropriate to be applied in clinical practice due to the simple and fast sample preparation based on protein precipitation, the low amount of patient sample necessary for the analysis (10 μL) and the total run time of 6.5 min. It was fully validated according to FDA and EMA guidelines on bioanalytical method validation. The linearity was assessed (R 2 within 0.9992-0.9983) over the concentration ranges of 0.3-250 ng/mL for palbociclib, 10-10000 ng/mL for ribociclib and 0.5-500 ng/mL for letrozole that properly cover the therapeutic plasma concentrations. A specific strategy was implemented to reduce the carryover phenomenon, formerly known for these CDKIs. This method was applied to quantify the C min of palbociclib, ribociclib and letrozole in plasma samples from patients enrolled in a clinical study. The same set of study samples was analysed twice in separate runs to assess the reproducibility of the method by means of the incurred samples reanalysis. The results corroborated the reliability of the analyte concentrations obtained with the bioanalytical method, already proved by the validation process. The percentage differences were always within ±10% for all the analytes and the R 2 of the correlation graph between the two quantifications was equal to 0.9994. OPEN ACCESS Citation: Posocco B, Buzzo M, Poetto AS, Orleni M, Gagno S, Zanchetta M, et al. (2020) Simultaneous quantification of palbociclib, ribociclib and letrozole in human plasma by a new LC-MS/MS method for clinical application. PLoS ONE 15(2): e0228822.

The introduction of imatinib, an oral tyrosine kinase inhibitor, as first-line standard therapy in patients with unresectable, metastatic, or recurrent gastro-intestinal stromal tumor (GIST), strongly improved their treatment outcomes. However, therapeutic drug monitoring (TDM) is recommended for this drug due to the large inter-individual variability in plasma concentration when standard dose is administered. A Cmin higher than 760 ng/mL was associated with a longer progression free survival. Thus, a LC-MS/MS method has been developed and fully validated to quantify imatinib and its active metabolite, norimatinib, in finger-prick dried blood spot (DBS). The influence of hematocrit, sample homogeneity, and spot size and the correlation between finger-prick and venous DBS measurements were also assessed. The method showed a good linearity (R2 > 0,996) between 50–7500 ng/mL for imatinib and 10–1500 ng/mL for norimatinib. Analytes were extracted from DBS samples by simply adding to 3 mm-discs 150 μL of acidified methanol containing IMA-D8. The collected extract was then injected on a LC Nexera system in-house configured for the on-line cleanup, coupled with an API-4000 QT. The chromatographic separation was conducted on a Synergi Fusion-RP column (4 μm, 2x50 mm) while the trapping column was a POROS R1/20 (20 μm, 2x30 mm). The total run time was 8.5 min. DBSs stored at room temperature in plastic envelopes containing a silica-gel drying bag were stable up to 16 months.The proposed method was applied to 67 clinical samples, showing a good correlation between patients’ finger-prick DBS and plasma concentrations, measured by the reference LC-MS/MS method, internally validated. Imatinib and norimatinib concentrations found in finger-prick DBS were adjusted by hematocrit or by an experimental correction factor to estimate the corresponding plasma measurements. At the best of our knowledge, the proposed LC-MS/MS method is the first analytical assay to measure imatinib and norimatinib in DBS samples.

No abstract

Over the last decade the importance of nitric oxide (NO) in plant signaling has emerged. Despite its recognized biological role, the sensitivity and effectiveness of the methods used for measuring NO concentration in plants are still under discussion. Among these, electron paramagnetic resonance (EPR) is a well-accepted technique to detect NO. In the present work we report the constraints of using 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) in biological samples as spin trap for quantitative measurement of NO. EPR analyses on Arabidopsis cell cultures and seedlings show that cPTIO(NNO) is degraded in a matter of few minutes while the (INO) compound, produced by cPTIO and NO reaction, has not been detected. Limitations of using this spin trap in plant systems for quantitative measurements of NO are discussed. As NO scavenger, cPTIO is widely used in combination with 4-amino-5-methylamino-2′,7′-difluorofluorescein (DAF-FM) fluorescent dye in plant research. However, the dependence of DAF-FM fluorescence on cPTIO and NO concentrations is not clearly defined so that the range of concentrations should be tightly selected. In this context, a systematic study on cPTIO NO scavenging properties has been performed, as it was still lacking for plant system applications. The results of this systematic analysis are discussed in terms of reliability of the use of cPTIO in the quantitative determination and scavenging of NO in plants and plant cultured cells.