Simple Modifications of Branched PEI Lead to Highly Efficient siRNA Carriers with Low Toxicity

Polymer carriers like PEI which proved their efficiency in DNA delivery were found to be far less effective for the applications with siRNA. In the current study, we generated a number of nontoxic derivates of branched PEI through modification of amines by ethyl acrylate, acetylation of primary amines, or introduction of negatively charged propionic acid or succinic acid groups to the polymer structure. The resulting products showed high efficiency in siRNA-mediated knockdown of target gene. In particular, succinylation of branched PEI resulted in up to 10-fold lower polymer toxicity in comparison to unmodified PEI. Formulations of siRNA with succinylated PEI were able to induce remarkable knockdown (80% relative to untreated cells) of target luciferase gene at the lowest tested siRNA concentration of 50 nM in Neuro2ALuc cells. The polyplex stability assay revealed that the efficiency of formulations which are stable in physiological saline is independent of the affinity of siRNA to the polymer chain. The improved properties of modified PEI as siRNA carrier are largely a consequence of the lower polymer toxicity. In order to achieve significant knockdown of target gene, the PEI-based polymer has to be applied at higher concentrations, required most probably for sufficient accumulation and proton sponge effects in endosomes. Unmodified PEI is highly toxic at such polymer concentrations. In contrast, the far less toxic modified analogues can be applied in concentrations required for the knockdown of target genes without side effects

Проблеми ісламу України в їх науковому відтворенні

The Pd/TOMPP-catalysed (TOMPP = tris(2-methoxyphenyl)phosphine) telomerisation of 1,3-butadiene was studied under solvent- and base-free conditions with phenolic substrates that can be potentially derived from lignin. Large differences in catalytic activity were observed, with reactivity increasing in the order of phenol, p-cresol, guaiacol, creosol and syringol. This reactivity trend can be attributed to the substrates’ relative nucleophilicities, as induced by the donating effects of the p-methyl and o-methoxy substituents. The chosen reaction conditions, i.e. temperature, ligand/metal and butadiene/substrate ratios, strongly influenced both the conversion and selectivity of the reaction. Remarkably, the composition of the reaction medium, i.e. the butadiene/substrate ratio, exerted a strong influence on the linear/branched ratio. High conversions and selectivities to the linear products are obtained when excess butadiene is used. The linear telomer products could be readily converted from O-alkylated to Calkylated phenolics via the thermal Claisen rearrangement. High conversions and selectivities were observed after 2 hours at 200 1C. Branched o-octadienyl phenols were obtained in all cases except for the syringol telomer which gave the linear p-octadienyl product exclusively

An experimental design approach to the chemical characterisation of pectin polysaccharides extracted from Cucumis melo Inodorus

Extracted pectins have been utilised in a number of applications in both the food and pharmaceutical industries where they are generally used as gelling agents, thickeners and stabilisers, although a number of pectins have been shown to be bioactive. These functional properties will depend upon extraction conditions. A statistical experimental design approach was used to study the effects of extraction conditions pH, time and temperature on pectins extracted from Cucumis melo Inodorus. The results show that the chemical composition is very sensitive to these conditions and that this has a great influence on for example the degree of branching. Higher temperatures, lower pHs and longer extraction times lead to a loss of the more acid labile arabinofuranose residues present on the pectin side chain. The fitting of regression equations relating yield and composition to extraction conditions can therefore lead to tailor-made pectins for specific properties and/ or applications

A Contour Integral Representation for the Dual Five-Point Function and a Symmetry of the Genus Four Surface in R6

The invention of the "dual resonance model" N-point functions BN motivated the development of current string theory. The simplest of these models, the four-point function B4, is the classical Euler Beta function. Many standard methods of complex analysis in a single variable have been applied to elucidate the properties of the Euler Beta function, leading, for example, to analytic continuation formulas such as the contour-integral representation obtained by Pochhammer in 1890. Here we explore the geometry underlying the dual five-point function B5, the simplest generalization of the Euler Beta function. Analyzing the B5 integrand leads to a polyhedral structure for the five-crosscap surface, embedded in RP5, that has 12 pentagonal faces and a symmetry group of order 120 in PGL(6). We find a Pochhammer-like representation for B5 that is a contour integral along a surface of genus five. The symmetric embedding of the five-crosscap surface in RP5 is doubly covered by a symmetric embedding of the surface of genus four in R6 that has a polyhedral structure with 24 pentagonal faces and a symmetry group of order 240 in O(6). The methods appear generalizable to all N, and the resulting structures seem to be related to associahedra in arbitrary dimensions.Comment: 43 pages and 44 figure

Dendrimers in gene delivery

Dendrimers have unique molecular architectures and properties that make them attractive materials for the development of nanomedicines. Key properties such as defined architecture and a high ratio of multivalent surface moieties to molecular volume also make these nanoscaled materials highly interesting for the development of synthetic (non-viral) vectors for therapeutic nucleic acids. Rational development of such vectors requires the link to be made between dendrimer structure and the morphology and physicochemistry of the respective nucleic acid complexes and, furthermore, to the biological performance of these systems at the cellular and systemic level. The review focuses on the current understanding of the role of dendrimers in those aspects of synthetic vector development. Dendrimer-based transfection agents have become routine tools for many molecular and cell biologists but therapeutic delivery of nucleic acids remains a challenge