Silver–titanium dioxide nanocomposites as effective antimicrobial and antibiofilm agents

Recent studies have revealed the existence of liver cancer stem cells (CSCs). Therefore, there is an urgent need for new and effective treatment strategies specific to liver CSCs. In this work, the poly(d,l-lactide-coglycolide) nanoparticles containing paclitaxel were prepared by emulsification-solvent evaporation method. The nanoparticles decorated with anti-CD133 antibody, termed targeted nanoparticles, were prepared by carbodiimide chemistry for liver CSCs. The physicochemical characteristics of the nanoparticles (i.e., encapsulation efficiency, particle size distribution, morphology, and in vitro release) were investigated. Cellular uptake and accumulation in tumor tissue of nanoparticles were observed. To assess anti-tumor activity of nanoparticles in vitro and in vivo, cell survival assay and tumor regression study were carried out using liver cancer cell lines (Huh7 and HepG2) and their xenografts. Particle size of targeted nanoparticles was 429.26 ± 41.53 nm with zeta potential of ?11.2 mV. Targeted nanoparticles possessed spherical morphology and high encapsulation efficiency (87.53 ± 5.9 %). The accumulation of targeted nanoparticles depends on dual effects of passive and active targeting. Drug-loaded nanoparticles showed cytotoxicity on the tumor cells in vitro and in vivo. Targeted nanoparticles resulted in significant improvement in therapeutic response through selectively eliminating CD133 positive subpopulation. These results suggested that the novel nanoparticles could be a promising candidate with excellent therapeutic efficacy for targeting liver CSCs.     

Sliding in a piecewise-smooth dynamical system with a hold-on effect

In this paper, we study a piecewise-smooth dynamical system of a Filippov type that has a specific discontinuity in the form of a hold-on term. The system resembles a driven dry-friction oscillator with the difference that the magnitude of the friction depends on the value of a local maximum of the oscillator displacement. Due to the hold-on term, the definition of the sliding region is not trivial. Along with a sliding region that is found analytically and is valid for any orbits, there exists a sliding region that we name ‘virtual’ because it is specific for each particular orbit. The existence of the virtual sliding region is explained by the specific discontinuity — the hold-on term — and the behavior associated with the sliding region and its boundaries can be considered as a new type of sliding-associated behavior.     

High‐Density Lipoprotein Nanoparticles Deliver RNAi to Endothelial Cells to Inhibit Angiogenesis

Systemic delivery of therapeutic nucleic acids to target cells and tissues outside of the liver remains a major challenge. A biomimetic high‐density lipoprotein nanoparticle (HDL NP) is synthesized for delivery of a cholesteryl‐modified therapeutic nucleic acid to vascular endothelial cells (ECs), a cell type naturally targeted by HDL. HDL NPs adsorb cholesteryl‐modified oligonucleotides and protect them from nuclease degradation. As proof of principle, we deliver RNAi targeting vascular endothelial growth factor receptor 2 (VEGFR2) to ECs to effectively silence target mRNA and protein expression in vitro. In addition, data show that treatment strongly attenuates in vivo neovascularization measured using a standard angiogenesis assay and in hypervascular tumor allografts where a striking reduction in tumor growth is observed. For effective delivery, HDL NPs require the expression of the cell surface protein scavenger receptor type‐B1 (SR‐B1). No toxicity of HDL NPs is measured in vitro or after in vivo administration. Thus, by using a biomimetic approach to nucleic acid delivery, data demonstrate that systemically administered RNAi–HDL NPs target SR‐B1 expressing ECs to deliver functional anti‐angiogenic RNAi as a potential treatment of cancer and other neovascular diseases.     

Description of liquid–gas phase transition in the frame of continuum mechanics

A new method of describing the liquid–gas phase transition is presented. It is assumed that the phase transition is characterized by a significant change of the particle density distribution as a result of energy supply at the boiling point that leads to structural changes but not to heating. Structural changes are described by an additional state characteristics of the system—the distribution density of the particles which is presented by an independent balance equation. The mathematical treatment is based on a special form of the internal energy and a source term in the particle balance equation. The presented method allows to model continua which have different specific heat capacities in liquid and in gas state.     

Structure-Directing Agents for the Synthesis of TiO(2) -Based Drug-Delivery Systems

A series of titanium oxides was prepared by using a surfactant-template method (STM) and used as a carrier for the sustained release of ibuprofen, which was chosen as a model drug. This STM provides an efficient route to TiO(2) matrices with both high surface area (when compared with those that were obtained by using traditional synthetic approaches) and well-defined mesoporous textures. Some parameters of the synthetic procedure were varied: pH value, surfactant, and thermal treatment. The physicochemical nature of the surface carriers were investigated by means of N(2) -physisorption measurements and FTIR spectroscopy. The effect of the amount of drug on the release kinetics was also investigated. The drug delivery was evaluated in vitro in four different physiological solutions (that simulated the gastrointestinal tract) to analyze the behavior of the TiO(2) -based systems if they were to be formulated as oral DDSs. Our optimized approach is a good alternative to the classical methods that are used to prepare efficient TiO(2) -based drug-delivery systems.     

Synthesis of quinolines via Friedländer reaction catalyzed by CuBTC metal-organic-framework

Friedl?nder condensation between 2-aminoaryl ketones and different carbonyl compounds, catalyzed by CuBTC was investigated by a combination of various experimental techniques and by density functional theory based modelling. CuBTC exhibiting hard Lewis acid character showed highly improved catalytic activity when compared with other molecular sieves showing high concentraion of Lewis acid sites, e.g. in BEA and (Al)SBA-15. Polysubstituted quinolines were synthesized via a Friedl?nder reaction catalyzed by CuBTC under the solvent-free conditions. High concentration of active sites in CuBTC together with the concerted effect of a pair of adjacent Cu(2+) coordinatively unsaturated active sites are behind a very high quinoline yield reached within a short reaction time. Results reported here make CuBTC a promising catalyst for other Lewis acid-promoted condensations, including those leading to biologically active compounds with a particular relevance for the pharmaceutical industry. The mechanism of a catalyzed Friedl?nder reaction investigated computationally is also reported.     

Paramagnetic 19F chemical shift probes that respond selectively to calcium or citrate levels and signal ester hydrolysis

Paramagnetic magnetic resonance chemical shift probes containing a proximal CF(3) group have been characterised. Different systems have been created that report reversible changes in calcium ion concentrations in the millimolar regime, signal the presence of citrate selectively in competitive aqueous media and allow the monitoring of remote ester/amide hydrolysis in relayed, irreversible transformations. Chemical shift non-equivalence is amplified by the presence of the proximate lanthanide ion, with a mean separation between the CF(3) group and the metal ion of 6.4 ? found for a thulium complex, in an X-ray structure of the metal complex aqua adduct. The enhanced rate of longitudinal relaxation of the (19)F nucleus allows faster data acquisition.     

Monolithic columns with optimized pore structure for molecular size-based separations of synthetic polymers

Monolithic capillary columns based on divinylbenzene were synthesized using different alcanols as porogens. Prepared columns were tested in separation of polystyrene standards according to their molar mass (MM) and were characterized by corresponding calibration graphs. It was demonstrated that a decrease of alcanol chain length from dodecanol to octanol resulted in a decrease of column permeability and in an improved column ability to separate polystyrene standards. In contrast, removing a good solvent from porogen mixture results in an increase of column permeability and in a decrease of column performance toward polystyrene standards. Optimized synthetic conditions included porogen composed of nonanol and toluene or mesytilene, and the column prepared with this porogen was capable of separating a mixture of 14 polystyrene standards with MM ranged from several millions to oligomers.     

ToxAlerts: A Web Server of Structural Alerts for Toxic Chemicals and Compounds with Potential Adverse Reactions

The article presents a Web-based platform for collecting and storing toxicological structural alerts from literature and for virtual screening of chemical libraries to flag potentially toxic chemicals and compounds that can cause adverse side effects. An alert is uniquely identified by a SMARTS template, a toxicological endpoint, and a publication where the alert was described. Additionally, the system allows storing complementary information such as name, comments, and mechanism of action, as well as other data. Most importantly, the platform can be easily used for fast virtual screening of large chemical datasets, focused libraries, or newly designed compounds against the toxicological alerts, providing a detailed profile of the chemicals grouped by structural alerts and endpoints. Such a facility can be used for decision making regarding whether a compound should be tested experimentally, validated with available QSAR models, or eliminated from consideration altogether. The alert-based screening can also be helpful for an easier interpretation of more complex QSAR models. The system is publicly accessible and tightly integrated with the Online Chemical Modeling Environment (OCHEM, http://ochem.eu ). The system is open and expandable: any registered OCHEM user can introduce new alerts, browse, edit alerts introduced by other users, and virtually screen his/her data sets against all or selected alerts. The user sets being passed through the structural alerts can be used at OCHEM for other typical tasks: exporting in a wide variety of formats, development of QSAR models, additional filtering by other criteria, etc. The database already contains almost 600 structural alerts for such endpoints as mutagenicity, carcinogenicity, skin sensitization, compounds that undergo metabolic activation, and compounds that form reactive metabolites and, thus, can cause adverse reactions. The ToxAlerts platform is accessible on the Web at http://ochem.eu/alerts , and it is constantly growing.     

On the applicability of elastic network normal modes in small-molecule docking

Incorporating backbone flexibility into protein-ligand docking is still a challenging problem. In protein-protein docking, normal mode analysis (NMA) has become increasingly popular as it can be used to describe the collective motions of a biological system, but the question of whether NMA can also be useful in predicting the conformational changes observed upon small-molecule binding has only been addressed in a few case studies. Here, we describe a large-scale study on the applicability of NMA for protein-ligand docking using 433 apo/holo pairs of the Astex data sets. On the basis of sets of the first normal modes from the apo structure, we first generated for each paired holo structure a set of conformations that optimally reproduce its C(α) trace with respect to the underlying normal mode subspace. Using AutoDock, GOLD, and FlexX we then docked the original ligands into these conformations to assess how the docking performance depends on the number of modes used to reproduce the holo structure. The results of our study indicate that, even for such a best-case scenario, the use of normal mode analysis in small-molecule docking is restricted and that a general rule on how many modes to use does not seem to exist or at least is not easy to find.