Nanofibers Fabricated Using Triaxial Electrospinning as Zero Order Drug Delivery Systems

A new strategy for creating functional trilayer nanofibers through triaxial electrospinning is demonstrated. Ethyl cellulose (EC) was used as the filament-forming matrix in the outer, middle, and inner working solutions and was combined with varied contents of the model active ingredient ketoprofen (KET) in the three fluids. Triaxial electrospinning was successfully carried out to generate medicated nanofibers. The resultant nanofibers had diameters of 0.74 ± 0.06 μm, linear morphologies, smooth surfaces, and clear trilayer nanostructures. The KET concentration in each layer gradually increased from the outer to the inner layer. In vitro dissolution tests demonstrated that the nanofibers could provide linear release of KET over 20 h. The protocol reported in this study thus provides a facile approach to creating functional nanofibers with sophisticated structural features

Electrospun pH-sensitive core-shell polymer nanocomposites fabricated using a tri-axial process

A modified tri-axial electrospinning process was developed for the generation of a new type of pH-sensitive polymer/lipid nanocomposite. The systems produced are able to promote both dissolution and permeation of a model poorly water-soluble drug. First, we show that it is possible to run a tri-axial procress with only one of the three fluids being electrospinnable. Using an electrospinnable middle fluid of Eudragit S100 (ES100) with pure ethanol as the outer solvent and an unspinnable lecithin-diclofenac sodium (PL-DS) core solution, nanofibers with linear morphology and clear core/shell structures can be fabricated continuously and smoothly. X-ray diffraction proved that these nanofibers are structural nanocomposites with the drug present in an amorphous state. In vitro dissolution tests demonstrated that the formulations could preclude release in acidic conditions, and that the drug was released from the fibers in two successive steps at neutral pH. The first step is the dissolution of the shell ES100 and the conversion of the core PL-DS into sub-micron sized particles. This frees some DS into solution, and later the remaining DS is gradually released from the PL-DS particles through diffusion. Ex vivo permeation results showed that the composite nanofibers give a more than two-fold uplift in the amount of DS passing through the colonic membrane as compared to pure DS; 74% of the transmitted drug was in the form of PL-DS particles. The new tri-axial electrospinning process developed in this work provides a platform to fabricate structural nanomaterials, and the core-shell polymer-PL nanocomposites we have produced have significant potential applications for oral colon-targeted drug delivery. STATEMENT OF SIGNIFICANCE: A modified tri-axial electrospinning is demonstrated to create a new type of core-shell pH-sensitive polymer/lipid nanocomposites, in which an electrospinnable middle fluid is exploited to support the un-spinnable outer and inner fluids. The structural nanocomposites are able to provide a colon-targeted sustained release and an enhanced permeation performance of diclofenac sodium. The developed tri-axial process can provide a platform for fabricating new structural nanomaterials with high quality. The strategy of a combined usage of polymeric excipients and phosphilipid in a core-shell format should provide new possibilities of developing novel drug delivery systems for efficacious oral administration of poorly-water soluble drugs

Exploring wettability difference-driven wetting by utilizing electrospun chimeric Janus microfiber comprising cellulose acetate and polyvinylpyrrolidone

In exploring the difference in the wettability of fibers with various structures, three inner constructions of fibers, namely, uniaxial, Janus and chimeric Janus, have been fabricated by electrospinning. In electrospun fibers, polyvinyl pyrrolidone and cellulose acetate were used as a polymer matrix and ketoprofen was used as a model drug. Morphologies and inner structures were respectively investigated by scanning electron microscopy (SEM) and Transmission electron microscopy (TEM). Physical states and compatibilities of materials were detected by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Water contact angle (WCA) tests were conducted to determine the difference between wettability and wetting time among assorted fiber membranes. Results showed that the wettability gradient could drive water movement and wetting, which resulted in the rapid decrease of the WCA, to prepare Janus and chimeric Janus fiber membranes compared with uniaxial fiber membranes. Otherwise, in vitro drug release experiments were carried out and four fitting models were applied in matching release profiles. The results showed that electrospun fiber membranes belonged to sustained-release systems and such membranes were influenced by drug diffusion and backbone corrosion effects. In this study, whether electrospun multilayer Janus fibers could affect wettability and drug release was investigated

Medicated Janus fibers fabricated using a Teflon-coated side-by-side spinneret.

A family of medicated Janus fibers that provides highly tunable biphasic drug release was fabricated using a side-by-side electrospinning process employing a Teflon-coated parallel spinneret. The coated spinneret facilitated the formation of a Janus Taylor cone and in turn high quality integrated Janus structures, which could not be reliably obtained without the Teflon coating. The fibers prepared had one side consisting of polyvinylpyrrolidone (PVP) K60 and ketoprofen, and the other of ethyl cellulose (EC) and ketoprofen. To modulate and tune drug release, PVP K10 was doped into the EC side in some cases. The fibers were linear and had flat morphologies with an indent in the center. They provide biphasic drug release, with the PVP K60 side dissolving very rapidly to deliver a loading dose of the active ingredient, and the EC side resulting in sustained release of the remaining ketoprofen. The addition of PVP K10 to the EC side was able to accelerate the second stage of release; variation in the dopant amount permitted the release rate and extent this phase to be precisely tuned. These results offer the potential to rationally design systems with highly controllable drug release profiles, which can complement natural biological rhythms and deliver maximum therapeutic effects

Electrospun medicated shellac nanofibers for colon-targeted drug delivery

Medicated shellac nanofibers providing colon-specific sustained release were fabricated using coaxial electrospinning. A solution of 7.5 g shellac and 1.5 g of ferulic acid (FA) in 10 mL ethanol was used as the core fluid, and a mixture of ethanol and N,N-dimethylformamide (8/10 v/v) as the shell. The presence of the shell fluid was required to prevent frequent clogging of the spinneret. The diameters of the fibers (D) can be manipulated by varying the ratio of shell to core flow rates (F), according to the equation D=0.52 F(-0.19). Scanning electron microscopy images revealed that fibers prepared with F values of 0.1 and 0.25 had linear morphologies with smooth surfaces, but when the shell fluid flow rate was increased to 0.5 the fiber integrity was compromised. FA was found to be amorphously distributed in the fibers on the basis of X-ray diffraction and differential scanning calorimetry results. This can be attributed to good compatibility between the drug and carrier: IR spectra indicated the presence of hydrogen bonds between the two. In vitro dissolution tests demonstrated that there was minimal FA release at pH 2.0, and sustained release in a neutral dissolution medium. The latter occurred through an erosion mechanism. During the dissolution processes, the shellac fibers were gradually converted into nanoparticles as the FA was freed into solution, and ultimately completely dissolved

Gd(III) complexes intercalated into hydroxy double salts as potential MRI contrast agents

The ion exchange intercalation of two Gd-based magnetic resonance imaging contrast agents into hydroxy double salts (HDSs) is reported. The presence of Gd(3+) diethylenetriaminepentaacetate and Gd(3+) diethylenetriaminepenta(methylenephosphonate) complexes in the HDS lattice after intercalation was confirmed by microwave plasma-atomic emission spectroscopy. The structural aspects of the HDS-Gd composites were studied by X-ray diffraction, with the intercalates having an interlayer spacing of 14.5-18.6 Å. Infrared spectroscopy confirmed the presence of characteristic vibration peaks associated with the Gd(3+) complexes in the intercalation compounds. The proton relaxivities of the Gd(3+) complex-loaded composites were 2 to 5-fold higher in longitudinal relaxivity, and up to 10-fold higher in transverse relaxivity, compared to solutions of the pure complexes. These data demonstrate that the new composites reported here are potentially potent MRI contrast agents

Metal-macrofauna interactions determine microbial community structure and function in copper contaminated sediments

Peer reviewedPublisher PD

Role of mprF1 and mprF2 in the Pathogenicity of Enterococcus faecalis

Aujourd hui, Enterococcus faecalis est considéré comme l un des plus importants agents pathogènes causant des maladies nosocomiales. En raison de sa résistance innée et acquise aux antibiotiques, l identification de nouvelles cibles pour le traitement de cette bactérie est une grande priorité. Le facteur Multiple Peptide Résistance (MprF), qui a été décrit en premier chez Staphylococcus aureus, modifie le phosphatidylglycérol avec de la lysine et réduit ainsi la charge négative de l enveloppe cellulaire. Ceci a comme conséquence d augmenter la résistance aux peptides antimicrobiens cationiques (PAC). Deux gènes paralogues putatifs (mprF1 et mprF2) ont été identifiés chez E. faecalis par recherche BLAST en utilisant le gène décrit chez S. aureus. Une caractérisation de ces deux gènes d E. faecalis ainsi que des mécanismes conduisant à une résistance aux PAC, pourrait aider à développer des nouvelles stratégies thérapeutiques contre ce pathogène. Deux mutants de délétion et un double mutant ont été construits par recombinaison homologue chez E. faecalis. L analyse des phospholipides des membranes cytoplasmiques des deux mutants mprF1 et mprF2 par chromatographie sur couche mince a montré que seule l inactivation de mprF2 inhibe la synthèse de trois amino-phosphatidlyglycérol distincts (comme la Lysine-PG, l Alanine-PG et l Arginine-PG). De plus, le mutant mprF2 est également plus sensible aux PAC que la souche sauvage. La capacité de formation d un biofilm est généralement considérée comme un facteur important de virulence, ce qui est également le cas pour les entérocoques. Le mutant mprF2 montre une capacité accrue dans ce phénomène. Ceci semble être du à une augmentation de la concentration d ADN extracellulaire dans le biofilm formé par ce mutant. Curieusement, cette augmentation est indépendante d une autolyse. Le mutant mprF2 est également plus résistant à l opsonophagocytose. Cependant, le gène mprF2 ne joue aucun rôle dans les bactériémies de souris et les endocardites de rats.En revanche, aucun phénotype n a été trouvé pour un mutant mprF1 jusqu à présent. Cette mutation ne modifie ni la synthèse de l aminoacyl-PG en condition de laboratoire ni la résistance aux PAC et à l opsonophagocytose. Par conséquent, il semble que mprF2 soit le seul gène mprF fonctionnel chez E. faecalis. Néanmoins, contrairement à d autres bactéries, mprF2 ne semble pas être un facteur de virulence majeur pour cette espèce.Enterococcus faecalis is regarded nowadays as one of the most important nosocomial pathogens. Due to its innate and acquired resistance to antibiotics, identification of new targets for antimicrobial treatment of E. faecalis is a high priority. The multiple peptides resistance factor (MprF), which was first described in Staphylococcus aureus, modifies phosphatidylglycerol with lysine and reduces the negative charge of the membrane, thus increasing resistance to cationic antimicrobial peptides (CAMPs). Two putative mprF paralogs (mprF1 and mprF2) were identified in E. faecalis by Blast search using the well-described S. aureus gene as a lead. A better understanding of these two genes and mechanisms leads to enterococcal resistance to CAMPs might help designing therapeutic strategies against this bacteria. Two single deletion mutants and double mutant in E. faecalis were created by homologues recombination. Analysis of cell membrane phospholipids from both mutants by thin-layer chromatography showed that inactivation of mprF2 abolished the synthesis of three distinct amino-phosphatidylglycerol (mostly likely Lysin-PG, Alanine-PG and Argine-PG). The CAMPs testing assay demonstrated that the deletion mutant of mprF2 was more susceptible to CAMPs than the wild type. Biofilm formation is usually regarded as a virulence factor which provides an important way for enterococci to cause infections. Inactivation of mprF2 led to increase the biofilm formation which we showed that it was due to the accumulation of eDNA in the biofilm, but the release of eDNA is independent from autolysis. The mprF2 mutant was resistance to killing by opsonophagocytosis more than wild type. However, the mprF2 gene plays no role in bacteremia in mice and rat endocarditis. Our results showed that non polar effect mprF1 mutant does not affect in the synthesis of aminoacyl-PG in the laboratory condition. It also has no effect on susceptible to CAMPs, opsonic killing and autolysis. Therefore, it seems that mprF2 is the only functional mprF gene in E. faecalis in the laboratory condition. Unlike mprF found in other bacteria, mprF does not seem to be a major virulence factor in enterococci.CAEN-BU Sciences et STAPS (141182103) / SudocSudocFranceF

The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma

The publisher's final edited version of this article is available at Oncogene. 2018 Oct;37(40):5435-5450. doi: 10.1038/s41388-018-0315-z. Epub 2018 Jun 5. Non-commercial use onlyThis study was funded by Cancer Research UK, the German Research Foundation (FOR2314) and the German Cancer Aid (111917)

Resource Quantity Affects Benthic Microbial Community Structure and Growth Efficiency in a Temperate Intertidal Mudflat

Estuaries cover <1% of marine habitats, but the carbon dioxide (CO2) effluxes from these net heterotrophic systems contribute significantly to the global carbon cycle. Anthropogenic eutrophication of estuarine waterways increases the supply of labile substrates to the underlying sediments. How such changes affect the form and functioning of the resident microbial communities remains unclear. We employed a carbon-13 pulse-chase experiment to investigate how a temperate estuarine benthic microbial community at 6.5°C responded to additions of marine diatom-derived organic carbon equivalent to 4.16, 41.60 and 416.00 mmol C m−2. The quantities of carbon mineralized and incorporated into bacterial biomass both increased significantly, albeit differentially, with resource supply. This resulted in bacterial growth efficiency increasing from 0.40±0.02 to 0.55±0.04 as substrates became more available. The proportions of diatom-derived carbon incorporated into individual microbial membrane fatty acids also varied with resource supply. Future increases in labile organic substrate supply have the potential to increase both the proportion of organic carbon being retained within the benthic compartment of estuaries and also the absolute quantity of CO2 outgassing from these environments