Alzheimer’s disease (AD) as a progressive and fatal neurodegenerative disease represents a huge unmet need for treatment. The low efficacy of current treatment methods is not only due to low drug potency but also due to the presence of various obstacles in the delivery routes. One of the main barriers is the blood–brain barrier. The increasing prevalence of AD and the low efficacy of current therapies have increased the amount of research on unraveling of disease pathways and development of treatment strategies. One of the interesting areas for the latter subject is biomaterials and their applications. This interest originates from the fact that biomaterials are very useful for the delivery of therapeutic agents, such as drugs, proteins, and/or cells, in order to treat diseases and regenerate tissues. Recently, manufacturing of nano-sized delivery systems has increased the efficacy and delivery potential of biomaterials. In this article, we review the latest developments with regard to the use of biomaterials for the treatment of AD, including nanoparticles and liposomes for delivery of therapeutic compounds and scaffolds for cell delivery strategies.

We describe the development of TMTH-SulfoxImine (TMTHSI) as a superior click reagent. This reagent combines a great reactivity, with small size and low hydrophobicity and compares outstandingly with existing click...

Mass spectrometry imaging (MSI) provides insight into the molecular distribution of a broad range of compounds and, therefore, is frequently applied in the pharmaceutical industry. Pharmacokinetic and toxicological studies deploy MSI to localize potential drugs and their metabolites in biological tissues but currently require other analytical tools to quantify these pharmaceutical compounds in the same tissues. Quantitative mass spectrometry imaging (Q-MSI) is a field with challenges due to the high biological variability in samples combined with the limited sample cleanup and separation strategies available prior to MSI. In consequence, more selectivity in MSI instruments is required. This can be provided by multiple reaction monitoring (MRM) which uses specific precursor ion-product ion transitions. This targeted approach is in particular suitable for pharmaceutical compounds because their molecular identity is known prior to analysis. In this work, we compared different analytical platforms to assess the performance of MRM detection compared to other MS instruments/MS modes used in a Q-MSI workflow for two drug candidates (A and B). Limit of detection (LOD), linearity, and precision and accuracy of high and low quality control (QC) samples were compared between MS instruments/modes. MRM mode on a triple quadrupole mass spectrometer (QqQ) provided the best overall performance with the following results for compounds A and B: LOD 35.5 and 2.5 μg/g tissue, R2 0.97 and 0.98 linearity, relative standard deviation QC <13.6%, and 97–112% accuracy. Other MS modes resulted in LOD 6.7–569.4 and 2.6–119.1 μg/g tissue, R2 0.86–0.98 and 0.86–0.98 linearity, relative standard deviation QC < 19.4 and < 37.5%, and 70–356% and 64–398% accuracy for drug candidates A and B, respectively. In addition, we propose an optimized 3D printed mimetic tissue model to increase the overall analytical throughput of our approach for large animal studies. The MRM imaging platform was applied as proof-of-principle for quantitative detection of drug candidates A and B in four dog livers and compared to LC-MS. The Q-MSI concentrations differed <3.5 times with the concentrations observed by LC-MS. Our presented MRM-based Q-MSI approach provides a more selective and high-throughput analytical platform due to MRM specificity combined with an optimized 3D printed mimetic tissue model. Graphical abstract

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Rationale The separation of isomeric compounds with major differences in their physiochemical and pharmacokinetic properties is of particular importance in pharmaceutical R&D. However, the structural assessment and separation of these compounds with current analytical techniques and methods are still a challenge. In this study, we describe strategies to separate the various structural and stereo‐isomers. Methods The separation of ten structural and stereo‐isomers was investigated using Trapped and Travelling Wave ion mobility spectrometry (TIMS and TWIMS). Different strategies including adduct ion formation with Na, Li, Ag and Cs as well as fragmentation before and after the ion mobility cell were applied to separate the isomeric compounds. Results All the counter ions (in particular Na) strongly coordinated with the test analytes in all the IMS systems. The highest resolving power was achieved for the sodium and lithium adducts using TIMS‐time‐of‐flight (TOF). However, some separation was attained on a Synapt HDMS system with its unique potential to monitor the ion mobility of the product ions. The elution order of the adduct ions was the same in all instruments, in which, unexpectedly, the para‐substituted isomer of the [M + Na]+ species had the lowest collision cross section followed by the meta‐ and ortho‐isomers. Conclusions The formation of adduct ions could facilitate the separation of structural and even stereo‐isomers by generating different molecular conformations. In addition, fragmenting isomers before or after the ion mobility cell is a valuable strategy to separate and also to assess the structures of adducts and different conformers.

Asymmetric catalysis is an essential tool in modern chemistry, but increasing environmental concerns demand the development of new catalysts based on cheap, abundant, and less toxic iron. As a result, Knölker-type catalysts have emerged as a promising class of iron catalysts for various chemical transformations, notably the hydrogenation of carbonyls and imines, while asymmetric versions are still under exploration to achieve optimal enantio-selectivities. In this work, we report a novel asymmetric design of a Knölker-type catalyst, in which the C2-rotational symmetric cyclopentadienone ligand possesses chiral substituents on the 2- and 5-positions near the active site. Four examples of the highly modular catalyst design were synthesized via standard organic procedures, and their structures were confirmed with NMR, IR, MS, and polarimetry analysis. Density functional theory (DFT) calculations were conducted to elucidate the spatial conformation of the catalysts, and therewith to rationalize the influence of structural alterations. Transfer- and H2-mediated hydrogenations were successfully established, leading to appreciable enantiomeric excesses (ee) values up to 70%. Amongst all reported Knölker-type catalysts, our catalyst design achieves one of the highest ee values for hydrogenation of acetophenone and related compounds.

Rationale Isomeric separation of prostanoids is often a challenge and requires chromatography and time‐consuming sample preparation. Multiple prostanoid isomers have distinct in vivo functions crucial for understanding the inflammation process, including prostaglandins E2 (PGE2) and D2 (PGD2). High‐resolution ion mobility spectrometry (IMS) based on linear ion transport in low‐to‐moderate electric fields and nonlinear ion transport in strong electric fields emerges as a broad approach for rapid separations prior to mass spectrometry. Methods Derivatization with Girard's reagent T (GT) was used to overcome inefficient ionization of prostanoids in negative ionization mode due to poor deprotonation of the carboxylic acid group. Three high‐resolution IMS techniques, namely linear cyclic IMS, linear trapped IMS, and nonlinear high‐field asymmetric waveform IMS, were compared for the isomeric separation and endogenous detection of prostanoids present in intestinal tissue. Results Direct infusion of GT‐derivatized prostanoids proved to increase the ionization efficiency in positive ionization mode by a factor of >10, which enabled detection of these molecules in endogenous concentration levels. The high‐resolution IMS comparison revealed its potential for rapid isomeric analysis of biologically relevant prostanoids. Strengths and weaknesses of both linear and nonlinear IMS are discussed. Endogenous prostanoid detection in intestinal tissue extracts demonstrated the applicability of our approach in biomedical research. Conclusions The applied derivatization strategy offers high sensitivity and improved stereoisomeric separation for screening of complex biological systems. The high‐resolution IMS comparison indicated that the best sensitivity and resolution are achieved by linear and nonlinear IMS, respectively.

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