Lactose-Functionalized Carbosilane Glycodendrimers Are Highly Potent Multivalent Ligands for Galectin-9 Binding: Increased Glycan Affinity to Galectins Correlates with Aggregation Behavior.

Galectins, the glycan binding proteins, and their respective carbohydrate ligands represent a unique fundamental regulatory network modulating a plethora of biological processes. The advances in galectin-targeted therapy must be based on a deep understanding of the mechanism of ligand-protein recognition. Carbosilane dendrimers, the well-defined and finely tunable nanoscaffolds with low toxicity, are promising for multivalent carbohydrate ligand presentation to target galectin receptors. The study discloses a synthetic method for two types of lactose-functionalized carbosilane glycodendrimers (Lac-CS-DDMs). Furthermore, we report their outstanding, dendritic effect-driven affinity to tandem-type galectins, especially Gal-9. In the enzyme-linked immunosorbent assay, the affinity of the third-generation multivalent dendritic ligand bearing 32 lactose units to Gal-9 reached nanomolar values (IC50 = 970 nM), being a 1400-fold more effective inhibitor than monovalent lactose for this protein. This demonstrates a game-changing impact of multivalent presentation on the inhibitory effect of a ligand as simple as lactose. Moreover, using DLS hydrodynamic diameter measurements, we correlated the increased affinity of the glycodendrimer ligands to Gal-3 and Gal-8 but especially to Gal-9 with the formation of relatively uniform and stable galectin/Lac-CS-DDM aggregates.

Carbosilane Glycodendrimers for Anticancer Drug Delivery: Synthetic Route, Characterization, and Biological Effect of Glycodendrimer-Doxorubicin Complexes.

The complexity of drug delivery mechanisms calls for the development of new transport system designs. Here, we report a robust synthetic procedure toward stable glycodendrimer (glyco-DDM) series bearing glucose, galactose, and oligo(ethylene glycol)-modified galactose peripheral units. In vitro cytotoxicity assays showed exceptional biocompatibility of the glyco-DDMs. To demonstrate applicability in drug delivery, the anticancer agent doxorubicin (DOX) was encapsulated in the glyco-DDM structure. The anticancer activity of the resulting glyco-DDM/DOX complexes was evaluated on the noncancerous (BJ) and cancerous (MCF-7 and A2780) cell lines, revealing their promising generation- and concentration-dependent effect. The glyco-DDM/DOX complexes show gradual and pH-dependent DOX release profiles. Fluorescence spectra elucidated the encapsulation process. Confocal fluorescence microscopy demonstrated preferential cancer cell internalization of the glyco-DDM/DOX complexes. The conclusions were supported by computer modeling. Overall, our results are consistent with the assumption that novel glyco-DDMs and their drug complexes are very promising in drug delivery and related applications.

Controlled Anchoring of (Phenylureido)sulfonamide-Based Receptor Moieties: An Impact of Binding Site Multiplication on Complexation Properties.

The repetition of urea-based binding units within the receptor structure does not only lead to monomer properties multiplication. As confirmed by spectroscopic studies, UV-Vis and 1H-NMR in classical or competitive titration mode, the attachment to a carrier allocates the active moieties to mutual positions predetermining the function of the whole receptor molecule. Bivalent receptors form self-aggregates. Dendritic receptors with low dihydrogen phosphate loadings offer a cooperative complexation mode associated with a positive dendritic effect. In higher dihydrogen phosphate concentrations, the dendritic branches act independently and the binding mode changes to 1:1 anion: complexation site. Despite the anchoring, the dendritic receptors retain the superior efficiency and selectivity of a monomer, paving the way to recyclable receptors, desirable for economic and ecological reasons.

Stereoselectivity in Glycosylation with Deoxofluorinated Glucosazide and Galactosazide Thiodonors.

Control of anomeric stereoselectivity in glycosylation with deoxofluorinated glycosyl donors is critical for assembly of fluorinated oligosaccharides. Here, we report the synthesis of benzylated 3-fluoro and 4-fluoro analogues of phenyl 1-thioglucosazide and galactosazide donors and evaluation of their stereoselectivity in glycosylation of a series of model carbohydrate acceptors using the Tf2O/Ph2SO promoter system. Low-temperature NMR revealed formation of covalent α-triflate and both anomers of oxosulfonium triflates under selected glycosylation conditions. This study demonstrates how the stereoselectivity depends on acceptor reactivity and glycosyl donor configuration. Reactive acceptors favor formation of 1,2- trans-ß-glycosides with both d- gluco and d- galacto donors, whereas poorly reactive acceptors favor formation of 1,2- cis-α-glycosides with d- galacto donors but are unselective with d- gluco donors.

Phosphonium carbosilane dendrimers - interaction with a simple biological membrane model.

The influence of three generations of five different phosphonium carbosilane dendrimers and one ammonium carbosilane dendrimer as a reference (PMe3, PBu3, P(Et2)2(CH2)3OH, PPh3, P(MeOPh)3 and NMe3, peripheral functional groups) on dimyristoylphosphatidylcholine (DMPC) or a lipid mixture dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DMPC/DMPG) of liposomes was studied by fluorescence polarization measurements and differential scanning calorimetry. All types of dendrimers interacted with neutral as well as negatively charged liposomes, but the strength and observed influence were different. Concentration, type of peripheral functional group modification and dendrimer generation were the main factors influencing the interaction. Generally, weak interactions as well as destabilization of the lipid membranes at low concentrations, regardless of liposome type, were observed in the case of DmPMe3, DmNMe3, DmPBu3 and DmP(Et2)2(CH2)3OH. Dendrimers with PPh3 and P(MeOPh)3 peripheral functional groups interacted much more strongly and increased the rigidity of liposomes. Electrostatic interactions, the hydrophobicity of substituents and charge shielding on the peripheral phosphonium group are important factors in the interaction. We suggest that, among the other types of dendrimers, the dendrimer with the P(MeOPh)3 peripheral functional group is a highly promising candidate for the design of a drug delivery system due to its positive charge, efficient interaction with lipidic membranes and low cytotoxicity.

Premature ovarian failure.

Premature ovarian failure is a heterogeneous disease that brings about several health risks. We must consider that the use of contraception in adolescent girls can mask this disease for a long time. Assisted reproductive technology has brought hope to women with premature ovarian failure to have their own child. Substitution of hormonal deficiency is important for eliminating unpleasant feelings associated with premature ovarian failure as well as for reducing the risk of late effects. Keywords: premature ovarian failure, hypergonadotropic hypogonadism, amenorrhea, gonadal dysgenesis, cryopreservation.

Preparations of spherical nanoparticles of chiral Cinchona alkaloid-based bridged silsesquioxanes and their use in heterogeneous catalysis of enantioselective reactions.

Two spherical nanoparticulate materials were prepared by base-catalyzed sol-gel hydrolysis/self-condensation of the bis-Cinchona alkaloid-phthalazine-based bridged bis(triethoxysilanes). For the purpose of comparing the catalytic properties, two compact materials were also prepared from the same precursors using a fluoride-catalyzed sol-gel process. All materials were characterized by SEM, TEM, solid-state 29Si NMR and 13C NMR, TGA, and FTIR. The prepared silsesquioxane-based materials were studied as potential heterogeneous catalysts for selected enantioselective reactions. The spherical material with regularly incorporated bis-quinine-phthalazine chiral units exhibited good to excellent enantioselectivities in osmium-catalyzed dihydroxylations of alkenes. Enantioselectivities observed in dihydroxylations of aromatic trans-alkenes were as excellent as those observed with the homogeneous catalyst (DHQ)2-PHAL. One compact and one nanoparticulate material was successfully recycled and reused five times without loss of enantioselectivity. Furthermore, both quinine-based and cinchonine-based materials were tested as heterogeneous organocatalysts for chlorolactonization of 4-arylpent-4-enoic acids. The materials showed only moderate enantioselectivities; however, these are the first heterogeneous catalysts for enantioselective chlorolactonization published so far.

An Insight into Anion Extraction by Amphiphiles: Hydrophobic Microenvironments as a Requirement for the Extractant Selectivity.

Coupling of electron-deficient urea units with aliphatic chains gives rise to amphiphilic compounds that bind to phosphate and benzoate anions in the hydrogen bonding competitive solvent (DMSO) with KAss = 6 580 M-1 and KAss = 4 100 M-1, respectively. The anchoring of these receptor moieties to the dendritic support does not result in a loss of anion binding and enables new applications. Due to the formation of a microenvironment in the dendrimer, the high selectivity of the prepared compound toward benzoate is maintained even in the presence of aqueous media during extraction experiments. In the presence of binding sites at 5 mM concentration, the amount of benzoate corresponding to the full binding site occupancy is transferred into the chloroform phase from its 10 mM aqueous solution. A thorough investigation of the extraction behavior of the dendrimer reported here, supported by a series of molecular dynamics simulations, provides new insight into the fundamental principles of extraction of inorganic anions by amphiphiles.

Biodistribution and toxicity assessment of methoxyphenyl phosphonium carbosilane dendrimers in 2D and 3D cell cultures of human cancer cells and zebrafish embryos.

The consideration of human and environmental exposure to dendrimers, including cytotoxicity, acute toxicity, and cell and tissue accumulation, is essential due to their significant potential for various biomedical applications. This study aimed to evaluate the biodistribution and toxicity of a novel methoxyphenyl phosphonium carbosilane dendrimer, a potential mitochondria-targeting vector for cancer therapeutics, in 2D and 3D cancer cell cultures and zebrafish embryos. We assessed its cytotoxicity (via MTT, ATP, and Spheroid growth inhibition assays) and cellular biodistribution. The dendrimer cytotoxicity was higher in cancer cells, likely due to its specific targeting to the mitochondrial compartment. In vivo studies using zebrafish demonstrated dendrimer distribution within the vascular and gastrointestinal systems, indicating a biodistribution profile that may be beneficial for systemic therapeutic delivery strategies. The methoxyphenyl phosphonium carbosilane dendrimer shows promise for applications in cancer cell delivery, but additional studies are required to confirm these findings using alternative labelling methods and more physiologically relevant models. Our results contribute to the growing body of evidence supporting the potential of carbosilane dendrimers as vectors for cancer therapeutics.

RADON MONITORING IN SELECTED KINDERGARTENS IN SLOVAKIA.

In 17 kindergartens in Slovakia indoor radon survey was performed over a period of 1 y. In selected kindergartens also continuous monitoring of indoor radon activity concentration was conducted for ~2 weeks, as well as soil radon measurements. Annual average of indoor radon concentration, measured using track detectors, ranged between 75 and 1810 Bq m-3. Soil radon concentration ranged from 13 to 320 kBq m-3. The relationship between activity concentrations measured in soil air and indoors has a linear character.

EMANATION OF RADON-222 FROM DIFFERENT SOIL TYPES AND SOIL GROUPS.

In this paper, we deal with measurement of 222Rn emanation coefficient (Ke) of soils using an accumulation method. We created a database of Ke values of dried soils for various soil types and soil groups, classified by the size of soil particles. For 18 different soil samples we obtained the Ke values in range 0.083-0.234. The analysis of radon emanation dependence on moisture for seven of these samples shows two different trends which were related to soil texture (clays or sands). Soils with predominant sandy particles prove weak dependence on moisture and Ke values from minimum value (at zero moisture) do not increase much (max 15% increase on every 5% of moisture), for soils with majority of clayey particles the moisture can affect the Ke more significantly (increase up to 60%).

RADON-PRONE AREAS IN SLOVAKIA PREDICTED BY RESCALED RADON POTENTIAL MAPS.

Several scientific studies have shown that high content of radon in the soil environment can be a precursor of increased indoor radon levels. Inhabited areas where elevated indoor radon concentration appears for natural (geogenic) reasons are commonly referred to as radon-prone areas. In this study, radon-prone areas in the Slovak Republic were predicted on the basis of radon potential maps after its specific rescaling. In total, 99 municipalities have been identified in Slovakia where the annual average indoor radon concentration is expected to exceed the reference level of 300 Bq m-3; five of those are even expected to exceed 1000 Bq m-3. In these municipalities it is then required to conduct a survey of indoor radon measurements. Compared with a nationwide survey, the proposed approach of searching for houses with potentially high radon exposure is more efficient.

Synthesis, Characterization, and Gas Adsorption Performance of Amine-Functionalized Styrene-Based Porous Polymers.

In recent years, porous materials have been extensively studied by the scientific community owing to their excellent properties and potential use in many different areas, such as gas separation and adsorption. Hyper-crosslinked porous polymers (HCLPs) have gained attention because of their high surface area and porosity, low density, high chemical and thermal stability, and excellent adsorption capabilities in comparison to other porous materials. Herein, we report the synthesis, characterization, and gas (particularly CO2) adsorption performance of a series of novel styrene-based HCLPs. The materials were prepared in two steps. The first step involved radical copolymerization of divinylbenzene (DVB) and 4-vinylbenzyl chloride (VBC), a non-porous gel-type polymer, which was then modified by hyper-crosslinking, generating micropores with a high surface area of more than 700 m2 g-1. In the following step, the polymer was impregnated with various polyamines that reacted with residual alkyl chloride groups on the pore walls. This impregnation substantially improved the CO2/N2 and CO2/CH4 adsorption selectivity.

ANALYSIS OF TIME SERIES OF RADON ACTIVITY CONCENTRATION IN OUTDOOR AIR AND THEIR RECONSTRUCTION.

222Rn (radon) is an ever-present radioactive component of the surface layer of the atmosphere. The knowledge of the shape of radon activity concentration (RAC) time series has several important applications in atmospheric studies. This study presents the results of RAC analysis according to Garzon et al. approach during the years 1991-2009, as well as attempts to reconstruct the shape of composite diurnal RAC cycles using either Garzon et al. original approach or other methods. From this study, it follows that in order to accurately reconstruct the mean diurnal RAC cycles for individual months in our locality (Central European region), the parameters have to be calibrated by local RAC and measured global solar radiation data. The original Garzon et al. approach underestimates the amplitude of mean diurnal RAC cycles during April-August by up to 10%, and overestimates the amplitude during September-March by up to 25%.

RESULTS OF LONG-TERM RADON MONITORING IN THE TYPICAL SLOVAK FAMILY HOUSE-A CASE STUDY.

This case study provides a view of the behavior of radon in an uninhabited house, the likes of which were built in thousands in Slovakia between 1950 and 1990. In one room of the house that was in contact with the subsoil, an average annual radon activity concentration (RAC) as high as 1088 Bq m-3 was found. A high radon supply to this room from the subsoil was identified in the corner of the room, and this correlated very well with the temperature difference between indoor and outdoor air. In this room, an atypical annual variation of RAC was found, with a maximum in September (1600 Bq m-3). In the other rooms on the ground floor, RACs at the level of 400-500 Bq m-3 were detected. In the rooms on the first floor, RACs of up to ~200 Bq m-3 were found.

DEVELOPMENT OF 222RN IN AIR SECONDARY STANDARD IN THE SLOVAK REPUBLIC.

Slovak Institute of Metrology received in 2016 funding for realisation of a set up of a radon chamber with AlphaGUARD as a secondary standard of 222Rn in air as one part of the project. This secondary standard will serve to provide the traceability for laboratories that deal with 222Rn measurements in environmental samples. This project is a response to the European Union legislation and provides metrological support for the development and implementation of the national radon action plan, which the member states of the European Union are committed to fulfil in accordance with Council Directive 2013/59/Euratom. During development of the radon chamber, the determination of its basic technical parameters, such as the exact determination of the container volume and the area of the inner walls of the radon chamber, many tightness tests of the chamber, the definition of homogeneous radon atmosphere parameters and bilateral comparisons, were realised.

Glucose-modified carbosilane dendrimers: Interaction with model membranes and human serum albumin.

Glycodendrimers are a novel group of dendrimers (DDMs) characterized by surface modifications with various types of glycosides. It has been shown previously that such modifications significantly decrease the cytotoxicity of DDMs. Here, we present an investigation of glucose-modified carbosilane DDMs (first-third-generation, DDM1-3Glu) interactions with two models of biological structures: lipid membranes (liposomes) and serum protein (human serum albumin, HSA). The changes in lipid membrane fluidity with increasing concentration of DDMs was monitored by spectrofluorimetry and calorimetry methods. The influence of glycodendrimers on serum protein was investigated by monitoring changes in protein fluorescence intensity (fluorescence quenching) and as protein secondary structure alterations by circular dichroism spectrometry. Generally, all generations of DDMGlu induced a decrease of membrane fluidity and interacted weakly with HSA. Interestingly, in contrast to other dendritic type polymers, the extent of the DDM interaction with both biological models was not related to DDM generation. The most significant interaction with protein was shown in the case of DDM2Glu, whereas DDM1Glu induced the highest number of changes in membrane fluidity. In conclusion, our results suggest that the flexibility of a DDM molecule, as well as its typical structure (hydrophobic interior and hydrophilic surface) along with the formation of larger aggregates of DDM2-3Glu, significantly affect the type and extent of interaction with biological structures.

RADON ACTIVITY CONCENTRATION IN WATERS OF SPRINGS IN SELECTED AREAS OF WESTERN SLOVAKIA.

This paper presents the results of measurements of radon activity concentration (RAC) in spring waters and natural wells in three mountains of Slovakia (Strázov Mountains, Povazský Inovec and Little Carpathians). These mountains provide drinking water for inhabitants of surrounding towns and villages. Little Carpathians is the most seismically active area in Slovakia. Povazský Inovec, where 2 out of 11 uranium deposits of Slovakia are located, is interesting due to increased uranium mineralization. We have collected samples from more than 170 natural water sources, many of which exceed the guide value of 100 Bq l-1, with a maximum value of 274 Bq l-1. The median of these data (15 Bq l-1) is also higher than the national median in groundwater (11.6 Bq l-1). From the obtained data, we have created maps representing RAC of groundwaters for the whole territory. These maps were also compared with the geological maps.

VARIATION OF RADON ACTIVITY CONCENTRATION IN SELECTED KINDERGARTENS IN SLOVAKIA.

Radon measurements were carried out in four kindergartens in Slovakia. RSKS detectors (Radosys Ltd., Hungary) and RamaRn (SUJCHBO, Czech Republic) were used for integral measurement in indoor air. AlphaGUARD (Saphymo, Germany) and TERA system (Tesla, Czech Republic) were used for continual measurement in indoor air. An annual variation with a maximum during the summer holidays was observed. Daily variation strongly depended on the ventilation of rooms. The average radon activity concentration per unit of time calculated from integral measurements was higher than that calculated for working time only.

DEVELOPMENT AND TESTING OF DEVICES FOR CONTINUOUS MONITORING OF RADON ACTIVITY CONCENTRATION IN WATERS.

Continuous radon measurement in waters is an appropriate tool for the study of its variations as well as for the clarification and understanding of the factors that cause these changes. In addition, sudden changes in radon activity concentration (RAC) in groundwater can be used to identify geodynamic activities and earthquake predictions. In this paper, two measuring systems for continuous monitoring of RAC in waters are presented and tested. One of them was designed for water sources with a high yield; the second one operates with a constant volume of a sample using a different method of 222Rn release from water. We present our first laboratory tests of continuous measurement of RAC in tap waters as well as the variations of RAC observed during a week.