Self‐aggregated nanoparticles of N‐dodecyl,N′‐glycidyl(chitosan) as pH‐responsive drug delivery systems for quercetin

In this study, pH‐responsive amphiphilic chitosan (CS) nanoparticles were used to encapsulate quercetin (QCT) for sustained release in cancer therapy. The novel CS derivatives were obtained by synthesis with 2,3‐epoxy‐1‐propanol, also known as glycidol, followed by acylation with dodecyl aldehyde. Characterization was performed by spectroscopic, viscosimetric, and size‐determination methods. Critical aggregation concentration, morphology, entrapment efficiency, drug release profile, cytotoxicity, and hemocompatibility studies were also carried out. The average size distribution of the self‐assembling nanoparticles measured by dynamic light scattering ranged from 140 to 300 nm. In vitro QCT release and Korsmeyer–Peppas model indicated that pH had a major role in drug release. Cytotoxicity assessments indicated that the nanoparticles were non‐cytotoxic. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay further revealed that QCT‐loaded nanoparticles could inhibit MCF‐7 cell growth. In vitro erythrocyte‐induced hemolysis indicated the good hemocompatibility of the nanoparticles. These results suggest that the synthesized copolymers might be potential carriers for hydrophobic drugs in cancer therapy. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 45678.     

Mismatch discrimination in oligonucleotide hybridization reactions using single strand binding protein. A surface plasmon fluorescence study

We describe the use of surface plasmon- and surface plasmon fieldenhanced fluorescence spectroscopy for the detection of hybridization reactions between surface-attached probe oligonucleotides and complement strands binding from solution. These targets, exhibiting different base mismatches relative to the probe 15-mer sequences, carry a fluorophore at their 5'-end thus allowing for sensitive detection and quantification of association, k_on, and dissociation, k_off, rate constants, as well as affinity constants, K_a. We demonstrate that by the competitive binding / replacement of single strand binding proteins the mismatch discrimination can be further enhanced.     

One Question,Multiple Answers: Biochemical and Biophysical Screening Methods Retrieve Deviating Fragment Hit Lists

Fragment‐based lead discovery is gaining momentum in drug development. Typically, a hierarchical cascade of several screening techniques is consulted to identify fragment hits which are then analyzed by crystallography. Because crystal structures with bound fragments are essential for the subsequent hit‐to‐lead‐to‐drug optimization, the screening process should distinguish reliably between binders and non‐binders. We therefore investigated whether different screening methods would reveal similar collections of putative binders. First we used a biochemical assay to identify fragments that bind to endothiapepsin, a surrogate for disease‐relevant aspartic proteases. In a comprehensive screening approach, we then evaluated our 361‐entry library by using a reporter‐displacement assay, saturation‐transfer difference NMR, native mass spectrometry, thermophoresis, and a thermal shift assay. While the combined results of these screening methods retrieve 10 of the 11 crystal structures originally predicted by the biochemical assay, the mutual overlap of individual hit lists is surprisingly low, highlighting that each technique operates on different biophysical principles and conditions.     

Dendrimeric silanes for formation of metallosilicates: new heterogeneous catalysts for the epoxidation of alkenes with tert-butylhydroperoxide

New metallosilicate catalysts were prepared by reacting a silanol capped dendrimer, Si[CH₂CH₂Si(CH₃)₂OH]₄ with MCp₂Cl₂ (M = Ti^IV, Mo^VI, W^VI and V^V). The resulting Si[CH₂CH₂>Si(CH₃)₂OMCp₂Cl]₄compounds were incorporated in a silica matrix by the sol–gel method. The catalytic activity of the metallosilicates after calcination revealed excellent activity and selectivity towards epoxidation of alkenes with tert-butylhydroperoxide. Maximum activity was observed with molybdenum-containing materials. Analysis of the catalytic activity revealed that the catalysts were truly heterogeneous.     

Identification of New N‐Acylhomoserine Lactone Signalling Compounds of Dinoroseobacter shibae DFL‐12T by Overexpression of luxI Genes

Bacteria of the Roseobacter clade are widespread in the ocean and occur in many different habitats. In the genome of Dinoroseobacter shibae DFL‐12, luxI homologous genes that encode synthases responsible for the formation of N‐acylhomoserine lactones (AHLs) have been described. These compounds are known autoinducers that regulate several biological traits—namely, flagella formation and cell differentiation—in D. shibae through quorum sensing. The AHLs produced by D. shibae mainly consisted of N‐octadecadienoylhomoserine lactone (C18:2‐AHL) and N‐octadecenoylhomoserine lactone (C18:1‐HSL). In the wild type these AHLs are synthesized only in low abundance. The luxI genes were therefore expressed in Escherichia coli; this resulted in the formation of AHLs mostly different from those found in the D. shibae wild type. A luxI₁‐deficient mutant of D. shibae was then reprovided with an overexpressed luxI₁ gene. This strain produced large amounts of C18:2‐AHL and C18:1‐AHL, allowing full characterization of these compounds by mass spectrometric techniques and derivatization. Synthesis of the proposed structures confirmed that the major compound is (2E,11Z)‐N‐octadeca‐2,11‐dienoylhomoserine lactone ( 6 , C18:2‐HSL), accompanied by (Z)‐N‐octadec‐11‐enoylhomoserine lactone ( 5 , C18:1‐HSL). AHL 6 has not been reported before from other organisms and contains an unusual 2E double bond.     

Challenges in nucleic acid‐lipid films for transfection

The use of surface‐based methods for the delivery of therapeutics has recently generated increasing interest. These platforms have tremendous potential to minimize detrimental side effects associated with systemic delivery by localizing the therapeutic vehicle, and thus provide higher local doses for improved efficacy. Cationic lipids are one of the most commonly used synthetic carriers for the delivery of genetic cargo, such as DNA and RNA. However, reports on the use of lipid‐based films for gene delivery are scarce. Here we investigate the use of a lipid‐based film for the in vitro delivery of plasmid DNA. Solid DNA‐lipid films show very low levels of transfection, while identical complexes prepared for bolus delivery provide high levels of transfection when used directly. We investigate the mechanism, whereby the activity of these solid‐state films is lost and suggest methods for circumventing these challenges and restoring the efficacy of these films as gene delivery platforms. © 2013 American Institute of Chemical Engineers AIChE J, 59: 3203–3213, 2013     

Genome-Wide Investigation of Multifocal and Unifocal Prostate Cancer—Are They Genetically Different?

Prostate cancer is widely observed to be biologically heterogeneous. Its heterogeneity is manifested histologically as multifocal prostate cancer, which is observed more frequently than unifocal prostate cancer. The clinical and prognostic significance of either focal cancer type is not fully established. To investigate prostate cancer heterogeneity, the genetic profiles of multifocal and unifocal prostate cancers were compared. Here, we report observations deduced from tumor-tumor comparison of copy number alteration data of both focal categories. Forty-one fresh frozen prostate cancer foci from 14 multifocal prostate cancers and eight unifocal prostate cancers were subjected to copy number variation analysis with the Affymetrix SNP 6.0 microarray tool. With the investigated cases, tumors obtained from a single prostate exhibited different genetic profiles of variable degrees. Further comparison identified no distinct genetic pattern or signatures specific to multifocal or unifocal prostate cancer. Our findings suggest that samples obtained from multiple sites of a single unifocal prostate cancer show as much genetic heterogeneity and variability as separate tumors obtained from a single multifocal prostate cancer.     

The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin⁻CD11b⁻Ly6C^hi CD115⁺, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.     

Electrodeposition of cobalt based ferro-magnetic metal nanowires in polycarbonate films with cylindrical nanochannels fabricated by heavy-ion-track etching

Polycarbonate films of thickness 30 μm were irradiated with heavy ions by applying a flux of 10⁸ ions cm⁻² to produce straight tracks perpendicular to the film surface. The tracks were preferentially etched in 6 M aqueous solution of sodium hydroxide to prepare cylindrical nanochannels. The channel diameters were tuned between 200 and 600 nm by varying the etching time. Co₈₁Cu₁₉ alloy nanowires were electrodeposited potentiostatically, while Co/Cu multilayered nanowires, consisting of alternating Co and Cu layers with thickness 10 nm, were synthesized by means of a pulse plating technique in channels of length 30 μm and diameter 200 nm. Co₈₁Cu₁₉ alloy nanowires showed an anisotropic magnetoresistance effect of 0.6%, and the giant magnetoresistance of Co/Cu multilayered nanowires reached up to 8.0%.     

Blends of Bio-Based Poly(Limonene Carbonate) with Commodity Polymers

In this study, blends of the bio-based poly(limonene carbonate) (PLimC) with different commodity polymers are investigated in order to explore the potential of PLimC toward generating more sustainable polymer materials by reducing the amount of petro- or food-based polymers. PLimC is employed as minority component in the blends. Next to the morphology and thermal properties of the blends the impact of PLimC on the mechanical properties of the matrix polymers is studied. The interplay of incompatibility and zero-shear melt viscosity contrast determines the blend morphology, leading for all blends to a dispersed droplet morphology for PLimC. Blends with polymers of similar structure to PLimC (i.e., aliphatic/aromatic polyester) show the best performance with respect to mechanical properties, whereas blends with polystyrene or poly(methyl methacrylate) are too brittle and polyamide 12 blends show very low elongations at break. In blends with Ecoflex (poly(butylene adipate-co-terephthalate)) and Arnitel EM400 (copoly(ether ester)) with poly(butylene terephthalate) hard and polytetrahydrofuran soft segments) a threefold increase in E-modulus can be achieved, while keeping the elongation at break at reasonable high values of ≈200%, making these blends highly interesting for applications.