Protein aggregation into amyloid fibrils is implicated in the pathogenesis of many neurodegenerative diseases. Engineered nanoparticles have emerged as a potential approach to alter the kinetics of protein fibrillation process. Yet, there are only a few reports describing the use of nanoparticles for inhibition of amyloid-β 40 (Aβ(40)) peptide aggregation, involved in Alzheimer's disease (AD). In the present study, we designed new uniform biocompatible amino-acid-based polymer nanoparticles containing hydrophobic dipeptides in the polymer side chains. The dipeptide residues were designed similarly to the hydrophobic core sequence of Aβ. Poly(N-acryloyl-L-phenylalanyl-L-phenylalanine methyl ester) (polyA-FF-ME) nanoparticles of 57 ± 6 nm were synthesized by dispersion polymerization of the monomer A-FF-ME in 2-methoxy ethanol, followed by precipitation of the obtained polymer in aqueous solution. Cell viability assay confirmed that no significant cytotoxic effect of the polyA-FF-ME nanoparticles on different human cell lines, e.g., PC-12 and SH-SY5Y, was observed. A significantly slow secondary structure transition from random coil to β-sheets during Aβ(40) fibril formation was observed in the presence of these nanoparticles, resulting in significant inhibition of Aβ(40) fibrillation kinetics. However, the polyA-FF-ME analogous nanoparticles containing the L-alanyl-L-alanine (AA) dipeptide in the polymer side groups, polyA-AA-ME nanoparticles, accelerate the Aβ(40) fibrillation kinetics. The polyA-FF-ME nanoparticles and the polyA-AA-ME nanoparticles may therefore contribute to a mechanistic understanding of the fibrillation process, leading to the development of therapeutic strategies against amyloid-related diseases.
Active gels present unique potential for the decontamination of chemical warfare agents (CWAs) as they strongly adhere to surfaces, thus allowing prolonged decontamination time. Herein, we present a decontamination hydrogel based on polyvinyl alcohol/borax, which contains sodium perborate (NaBO 3 ), as an in situ source of the active ingredient hydrogen peroxide. Developed as a binary formulation, this gel instantly forms and effectively sticks when sprayed on various matrices, including porous and vertically positioned matrices. The gel efficiently detoxified the CWAs sarin (GB), O-ethyl S-2-(diisopropylamino)ethyl methylphosphonothioate (VX), and sulfur mustard (HD) in test tubes (2 μL CWA/0.5 mL gel) to provide nontoxic products with reaction half-lives of <3, 45 and 113 min, respectively. The gel was also shown to efficiently decontaminate surfaces contaminated with VX (5−7 mg, 8−12 mL of gel, i.e., >99%) and to prevent GB evaporation, as proven by laboratory wind tunnel experiments. The universal decontamination abilities of this mild hydrogel, as well as its facile application and removal processes suggest that it holds high potential for future development as a new CWA decontamination tool.
Bisphosphonates (BPs) are non‐hydrolyzable pyrophosphate analogs with high affinity to hydroxyapatite due to their ability to create bidentate or tridentate chelates with calcium ions. Consequently, BP lead to strong interactions with dentin, enamel, and bones. BPs (especially those bearing OH) accelerate osteoblasts action, while strongly inhibiting osteoclasts, thus contributing to enhanced bone formation. Recently, several novel BP non‐biodegradable and biodegradable vinylic monomers were synthesized in our laboratory. This article provides a detailed description regarding the synthesis of a unique biodegradable BP monomer and near infrared (NIR) fluorescent nano/microparticles for diagnosis and therapy of bone malignancy. These particles were prepared by dispersion copolymerization of three monomers: methacrylate polyethylene glycol (PEG) BP, N‐(3‐aminopropyl) methacrylamide, and the crosslinker monomer tetra(ethyleneglycol) diacrylate. The PEG‐BP nanoparticles size was controlled by changing various polymerization parameters. These BP particles possess dual functionality: covalent attachment of a dye (e.g., NIR fluorescent dye) or drug to the nanoparticles through the primary amine groups belonging to the aminopropyl methacrylamide monomeric units and chelation to the bone mineral hydroxyapatite through the BP groups belonging to the methacrylate PEG‐BP monomeric units. Body distribution of the optimal crosslinked BP nanoparticles was tested on a chicken embryo model via intravenous administration. This study indicated that the fluorescence intensity of all the organs except the bones decreased significantly within 48 h (p < 0.05) while that of the bones hardly changed over that time (p > 0.05). In addition, a relatively long half‐life time of these nanoparticles in blood has been demonstrated, probably due to the PEG moiety. Copyright © 2014 John Wiley & Sons, Ltd.
Potential energy surfaces for the nucleophilic displacements at phosphorus in dimethyl methyl-, chloromethyl-, dichloromethyl-, and trichloromethylphosphonates have been computed at the B3LYP/6-31+G* level of theory, using IEF-PCM to account for the solvent effect. The results reveal that sequential addition of chlorine substituents on the methyl phosphonates increases the stability of transition states and intermediates which facilitate P-C bond cleavage. Thus, while nonsubstituted dimethyl methylphosphonate and dimethyl chloromethylphosphonate may undergo exclusive P-O bond cleavage, the trichlorinated analogue exclusively undergoes P-C bond dissociation. Dichloromethylphosphonic acid derivatives were found to be borderline cases: while P-O fission is the preferred process, P-C scission might also be feasible. The increase in stability of the corresponding transition states and intermediates can account for the enhancement in the apicophilicity of the methyl ligand upon substitution with chlorine atoms.
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