Vesicular systems for delivering conventional small organic molecules and larger macromolecules to and through human skin

The history of using vesicular systems for drug delivery to and through skin started nearly three decades ago with a study utilizing phospholipid liposomes to improve skin deposition and reduce systemic effects of triamcinolone acetonide. Subsequently, many researchers evaluated liposomes with respect to skin delivery, with the majority of them recording localized effects and relatively few studies showing transdermal delivery effects. Shortly after this, Transfersomes were developed with claims about their ability to deliver their payload into and through the skin with efficiencies similar to subcutaneous administration. Since these vesicles are ultradeformable, they were thought to penetrate intact skin deep enough to reach the systemic circulation. Their mechanisms of action remain controversial with diverse processes being reported. Parallel to this development, other classes of vesicles were produced with ethanol being included into the vesicles to provide flexibility (as in ethosomes) and vesicles were constructed from surfactants and cholesterol (as in niosomes). Thee ultradeformable vesicles showed variable efficiency in delivering low molecular weight and macromolecular drugs. This article will critically evaluate vesicular systems for dermal and transdermal delivery of drugs considering both their efficacy and potential mechanisms of action.

Effect of plasma insulin and branched-chain amino acids on skeletal muscle protein synthesis in fasted lambs

The increase in fractional rate of protein synthesis (K-s) in the skeletal muscle of growing rats during the transition from fasted to fed state has been explained by the synergistic action of a rise in plasma insulin and branched-chain amino acids (BCAA). Since growing lambs Also exhibit an increase in K-s with level of feed intake, the objective of the present study was to determine if this synergistic relationship between insulin and BCAA also occurs in ruminant animals. Six 30 kg fasted (72 h) lambs (8 months of age) received each of four treatments, which were based on continuous infusion into the jugular vein for 6 h of: (1) saline (155 mmol NaCl/l); (2) a mixture of BCAA (0.778 mumol leucine, 0.640 mumol isoleucine and 0.693 mumol valine/min.kg); (3) 18.7 mumol glucose/min.kg (to induce endogenous insulin secretion): (4) co-infusion of BCAA and glucose. Within each period all animals received the same isotope of phenylalanine, (Phe) as follows: (1) L-[1-C-13]Phe; (2) L-phenyl-[ring H-2(5)]-alanine; (3) L-[N-15]Phe; (4) L-[ring 2,6-H-3]Phe. Blood was sampled serially during infusions to measure plasma concentrations of insulin, glucose and amino acids, and plasma free Phe isotopic activity; biopsies were taken 6 h after the beginning of infusions to determine K-s in in. longissimus dorsi and vastus muscle. Compared with control (saline-infused) lambs, K-s was increased by an average of 40% at the end of glucose infusion, but this effect was not statistically significant in either of the muscles sampled. BCAA infusion, alone or in combination with glucose, also had no significant effect on K-s compared with control sheep. K-s was approximately 60% greater for vastus muscle than for m. longissimus dorsi (P<0.01), regardless of treatment. It is concluded that there are signals other than insulin and BCAA that are responsible for the feed-induced increase in K-s in muscle of growing ruminant animals.

Legumes regulate Rhizobium bacteroid development and persistence by the supply of branched-chain amino acids

One of the largest contributions to biologically available nitrogen comes from the reduction of N-2 to ammonia by rhizobia in symbiosis with legumes. Plants supply dicarboxylic acids as a carbon source to bacteroids, and in return they receive ammonia. However, metabolic exchange must be more complex, because effective N-2 fixation by Rhizobium leguminosarum bv viciae bacteroids requires either one of two broad-specificity amino acid ABC transporters (Aap and Bra). It was proposed that amino acids cycle between plant and bacteroids, but the model was unconstrained because of the broad solute specificity of Aap and Bra. Here, we constrain the specificity of Bra and ectopically express heterologous transporters to demonstrate that branched-chain amino acid (LIV) transport is essential for effective N-2 fixation. This dependence of bacteroids on the plant for LIV is not due to their known down-regulation of glutamate synthesis, because ectopic expression of glutamate dehydrogenase did not rescue effective N-2 fixation. Instead, the effect is specific to LIV and is accompanied by a major reduction in transcription and activity of LIV biosynthetic enzymes. Bacteroids become symbiotic auxotrophs for LIV and depend on the plant for their supply. Bacteroids with aap bra null mutations are reduced in number, smaller, and have a lower DNA content than wild type. Plants control LIV supply to bacteroids, regulating their development and persistence. This makes it a critical control point for regulation of symbiosis. MICROBIOLOGY

Fragrance release from the surface of branched poly(amide)s

Enzymes are powerful tools in organic synthesis that are able to catalyse a wide variety of selective chemical transformations under mild and environmentally friendly conditions. Enzymes such as the lipases have also found applications in the synthesis and degradation of polymeric materials. However, the use of these natural catalysts in the synthesis and the post-synthetic modification of dendrimers and hyperbranched molecules is an application of chemistry yet to be explored extensively. In this study the use of two hydrolytic enzymes, a lipase from Candida cylindracea and a cutinase from Fusarium solani pisii, were investigated in the selective cleavage of ester groups situated on the peripheral layer of two families of branched polyamides. These branched polyamides were conjugated to simple fragrances citronellol and L-menthol via ester linkages. Hydrolysis of the ester linkage between the fragrances and the branched polyamide support was carried out in aqueous buffered systems at slightly basic pH values under the optimum operative conditions for the enzymes used. These preliminary qualitative investigations revealed that partial cleavage of the ester functionalities from the branched polyamide support had occurred. However, the ability of the enzymes to interact with the substrates decreased considerably as the branching density, the rigidity of the structure and the bulkiness of the polyamide-fragrance conjugates increased.

Poly(ethylene glycol)-supported nitroxyls: branched catalysts for the selective oxidation of alcohols

Nitroxyl radicals such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) are highly selective oxidation catalysts for the conversion of primary alcohols into the corresponding aldehydes. In this study, direct tethering of TEMPO units onto linear poly(ethylene glycol) (PEG) has afforded macromolecular catalysts that exhibit solubility in both aqueous and organic solvents. Recovery of the dissolved polymer-supported catalyst has been carried out by precipitation with a suitable solvent such as diethyl ether. The high catalyst activities and selectivities associated traditionally with nitroxyl-mediated oxidations of alcohols are retained by the series of "linker-less" linear PEG-TEMPO catalysts in which the TEMPO moiety is coupled directly to the PEG support. Although the selectivity remains unaltered, upon recycling of the linker-less polymer-supported catalysts, extended reaction times are required to maintain high yields of the desired carbonyl compounds. Alternatively, attachment of two nitroxyl radicals onto each functionalized PEG chain terminus via a 5-hydroxyisophthalic acid linker affords branched polymer-supported catalysts. In stark contrast to the linker-less catalysts, these branched nitroxyls exhibit catalytic activities up to five times greater than 4-methoxy-TEMPO alone under similar conditions. In addition, minimal decrease in catalytic activity is observed upon recycling of these branched macromolecular catalysts via solvent-induced precipitation. The high catalytic activities and preservation of activity upon recycling of these branched systems is attributed to enhanced regeneration of the nitroxyl species as a result of intramolecular syn-proportionation.

Comparing tube models for predicting the linear rheology of branched polymer melts

The hierarchical and "bob" (or branch-on-branch) models are tube-based computational models recently developed for predicting the linear rheology of general mixtures of polydisperse branched polymers. These two models are based on a similar tube-theory framework but differ in their numerical implementation and details of relaxation mechanisms. We present a detailed overview of the similarities and differences of these models and examine the effects of these differences on the predictions of the linear viscoelastic properties of a set of representative branched polymer samples in order to give a general picture of the performance of these models. Our analysis confirms that the hierarchical and bob models quantitatively predict the linear rheology of a wide range of branched polymer melts but also indicate that there is still no unique solution to cover all types of branched polymers without case-by-case adjustment of parameters such as the dilution exponent alpha and the factor p(2) which defines the hopping distance of a branch point relative to the tube diameter. An updated version of the hierarchical model, which shows improved computational efficiency and refined relaxation mechanisms, is introduced and used in these analyses.

Conformational modulation of sequence recognition in synthetic macromolecules

The different triplet sequences in high molecular weight aromatic copolyimides comprising pyromellitimide units ("I") flanked by either ether-ketone ("K") or ether-sulfone residues ("S") show different binding strengths for pyrene-based tweezer-molecules. Such molecules bind primarily to the diimide unit through complementary π-π-stacking and hydrogen bonding. However, as shown by the magnitudes of 1H NMR complexation shifts and tweezer-polymer binding constants, the triplet "SIS" binds tweezer-molecules more strongly than "KIS" which in turn bind such molecules more strongly than "KIK". Computational models for tweezer-polymer binding, together with single-crystal X-ray analyses of tweezer-complexes with macrocyclic ether-imides, reveal that the variations in binding strength between the different triplet sequences arise from the different conformational preferences of aromatic rings at diarylketone and diarylsulfone linkages. These preferences determine whether or not chain-folding and secondary π−π-stacking occurs between the arms of the tweezermolecule and the 4,4'-biphenylene units which flank the central diimide residue.

In vitro fermentation of linear and alpha-1,2-branched dextrans by the human fecal microbiota

The role of structure and molecular weight in fermentation selectivity in linear α-1,6 dextrans and dextrans with α-1,2 branching was investigated. Fermentation by gut bacteria was determined in anaerobic, pH-controlled fecal batch cultures after 36 h. Inulin (1%, wt/vol), which is a known prebiotic, was used as a control. Samples were obtained at 0, 10, 24, and 36 h of fermentation for bacterial enumeration by fluorescent in situ hybridization and short-chain fatty acid analyses. The gas production of the substrate fermentation was investigated in non-pH-controlled, fecal batch culture tubes after 36 h. Linear and branched 1-kDa dextrans produced significant increases in Bifidobacterium populations. The degree of α-1,2 branching did not influence the Bifidobacterium populations; however, α-1,2 branching increased the dietary fiber content, implying a decrease in digestibility. Other measured bacteria were unaffected by the test substrates except for the Bacteroides-Prevotella group, the growth levels of which were increased on inulin and 6- and 70-kDa dextrans, and the Faecalibacterium prausnitzii group, the growth levels of which were decreased on inulin and 1-kDa dextrans. A considerable increase in short-chain fatty acid concentration was measured following the fermentation of all dextrans and inulin. Gas production rates were similar among all dextrans tested but were significantly slower than that for inulin. The linear 1-kDa dextran produced lower total gas and shorter time to attain maximal gas production compared to those of the 70-kDa dextran (branched) and inulin. These findings indicate that dextrans induce a selective effect on the gut flora, short-chain fatty acids, and gas production depending on their length.

Lightly branched comb polyesters: application in fast drying solvent-borne coating formulations

Novel oxazoline-based comb-polymers possessing linoleyl or oleic side chains have been synthesized and used to produce low viscosity coatings. Inclusion of the polymers in model paint formulations results in coatings that exhibit faster drying times than commercially available alkyd resin formulations. The comb polymers were produced from diol substituted oxazoline monomers that were synthesized through a scalable, solvent free protocol and purified by simple recrystallisation. Co-polymerisation of the oxazolines with adipic acid at 160 °C in the bulk resulted in the targeted polyester comb type polymers. The polymers were soluble in a range of organic solvents and compatible with commercial alkyd resins. Model paint formulations containing up to 40 wt% of the linoleyl-based comb polymers exhibited a dramatic reduction in viscosity (from 35 to 13 Poise at 25 °C) with increasing quantities of polymer added. Dynamic mechanical analysis (DMA) studies revealed that the drying rate of the model paint formulations containing the comb polymers was enhanced when compared with that of commercial alkyd resins.

Influence of molecular composition on the development of microstructure from sheared polyethylene melts: Molecular and lamellar templating

A combination of in situ and ex situ X-ray scattering techniques and transmission electron microscopy has been used to study the crystallization behaviour of polyethylene, following the imposition of melt shear. In the case of a branched material, the imposition of shear flow up to a rate of 30 s(-1) was found to induce no anisotropy. Although shearing the linear material only ever induced a very small degree of anisotropy in the melt, for shear rates > 0.15 s(-1), subsequent crystallization resulted in increasing anisotropy. Blends of the above two polyethylenes were produced, in which the linear material constituted the minority fraction (similar to 10%). Isothermal crystallization at temperatures where extensive crystallization of the branched material does not occur demonstrated that the behaviour of the linear component of the sheared blend mirrored that of the linear polyethylene alone. However, in addition, it was found that when crystallized in the presence of an oriented morphology, the branched polymer also formed anisotropic structures. We have termed the process templating, in which the crystallization behaviour of the bulk of the system (similar to 90% branched material) is completely altered (spherulitic to oriented lamellar) by mapping it onto a pre-existing minority structure (similar to 10% linear polymer). (c) 2006 Elsevier Ltd. All rights reserved.

Linear viscoelasticity from molecular dynamics simulation of entangled polymers

The linear viscoelastic (LVE) spectrum is one of the primary fingerprints of polymer solutions and melts, carrying information about most relaxation processes in the system. Many single chain theories and models start with predicting the LVE spectrum to validate their assumptions. However, until now, no reliable linear stress relaxation data were available from simulations of multichain systems. In this work, we propose a new efficient way to calculate a wide variety of correlation functions and mean-square displacements during simulations without significant additional CPU cost. Using this method, we calculate stress−stress autocorrelation functions for a simple bead−spring model of polymer melt for a wide range of chain lengths, densities, temperatures, and chain stiffnesses. The obtained stress−stress autocorrelation functions were compared with the single chain slip−spring model in order to obtain entanglement related parameters, such as the plateau modulus or the molecular weight between entanglements. Then, the dependence of the plateau modulus on the packing length is discussed. We have also identified three different contributions to the stress relaxation:  bond length relaxation, colloidal and polymeric. Their dependence on the density and the temperature is demonstrated for short unentangled systems without inertia.