Delayed hepatic uptake of multi-phosphonic acid poly(ethylene glycol) coated iron oxide measured by real-time Magnetic Resonance Imaging

We report on the synthesis, characterization, stability and pharmacokinetics of novel iron based contrast agents for magnetic resonance imaging (MRI). Statistical copolymers combining multiple phosphonic acid groups and poly(ethylene glycol) (PEG) were synthesized and used as coating agents for 10 nm iron oxide nanocrystals. In vitro, protein corona and stability assays show that phosphonic acid PEG copolymers outperform all other coating types examined, including low molecular weight anionic ligands and polymers. In vivo, the particle pharmacokinetics is investigated by monitoring the MRI signal intensity from mouse liver, spleen and arteries as a function of the time, between one minute and seven days after injection. Iron oxide particles coated with multi-phosphonic acid PEG polymers are shown to have a blood circulation lifetime of 250 minutes, i.e. 10 to 50 times greater than that of recently published PEGylated probes and benchmarks. The clearance from the liver takes in average 2 to 3 days and is independent of the core size, coating and particle stability. By comparing identical core particles with different coatings, we are able to determine the optimum conditions for stealth MRI probes.Comment: 19 pages 8 figures, RSC Advances, 201

Interactions between sub-10 nm iron and cerium oxide nanoparticles and 3T3 fibroblasts : the role of the coating and aggregation state

Recent nanotoxicity studies revealed that the physico-chemical characteristics of engineered nanomaterials play an important role in the interactions with living cells. Here, we report on the toxicity and uptake of the cerium and iron oxide sub-10 nm nanoparticles by NIH/3T3 mouse fibroblasts. Coating strategies include low-molecular weight ligands (citric acid) and polymers (poly(acrylic acid), MW = 2000 g mol-1). Electrostatically adsorbed on the surfaces, the organic moieties provide a negatively charged coating in physiological conditions. We find that most particles were biocompatible, as exposed cells remained 100% viable relative to controls. Only the bare and the citrate-coated nanoceria exhibit a slight decrease of the mitochondrial activity for cerium concentrations above 5 mM (equivalent to 0.8 g L-1). We also observe that the citrate-coated particles are internalized by the cells in large amounts, typically 250 pg per cell after a 24 h incubation for iron oxide. In contrast, the polymer-coated particles are taken up at much lower rates (< 30 pg per cell). The strong uptake shown by the citrate-coated particles is related to the destabilization of the dispersions in the cell culture medium and their sedimentation down to the cell membranes. In conclusion, we show that the uptake of nanomaterials by living cells depends on the coating of the particles and on its ability to preserve the colloidal nature of the dispersions.Comment: 9 figures, 2 table

Preparation of parenteral nanocrystal suspensions of etoposide from the excipient free dry state of the drug to enhance in vivo antitumoral properties

Nanoparticle technology in cancer chemotherapy is a promising approach to enhance active ingredient pharmacology and pharmacodynamics. Indeed, drug nanoparticles display various assets such as extended blood lifespan, high drug loading and reduced cytotoxicity leading to better drug compliance. In this context, organic nanocrystal suspensions for pharmaceutical use have been developed in the past ten years. Nanocrystals offer new possibilities by combining the nanoformulation features with the properties of solid dispersed therapeutic ingredients including (i) high loading of the active ingredient, (ii) its bioavailability improvement, and (iii) reduced drug systemic cytotoxicity. However, surprisingly, no antitumoral drug has been marketed as a nanocrystal suspension until now. Etoposide, which is largely used as an anti-cancerous agent against testicular, ovarian, small cell lung, colon and breast cancer in its liquid dosage form, has been selected to develop injectable nanocrystal suspensions designed to be transferred to the clinic. The aim of the present work is to provide optimized formulations for nanostructured etoposide solutions and validate by means of in vitro and in vivo evaluations the efficiency of this multiphase system. Indeed, the etoposide formulated as a nanosuspension by a bottom-up approach showed higher blood life span, reduced tumor growth and higher tolerance in a murine carcinoma cancer model. The results obtained are promising for future clinical evaluation of these etoposide nanosuspensions

When The News Was Sung: Ballads as News Media in Early Modern Europe

News songs differ in crucial ways to the other news media of the early modern period like newsletters, newspapers, or diplomatic correspondence – they differ even from the prose broadsheets and pamphlets that they so closely resemble. As historians of news we need to ask different kinds of questions of these multi-media artifacts. For example, how does the presentation in a performative genre affect the dissemination and reception of information about events? What part do orality and aurality play in how the news was sold and received? Here the activities and social status of street singers play an important role. We must consider the production, format and distribution of these songs in order to understand their impact. We also need to pay attention to the conjunction between text and melody, and the ways in which this affected the presentation of a news event. On a broader scale, what kind of information can ballads provide about specific news events that other documents cannot or will not provide? Can they offer us a new medium by which to interpret historical events? And lastly, how should historians deal with these profoundly emotive texts? The combination of sensationalist language and affecting music meant that songs had the potential to provoke a more powerful response than any other contemporary news source, and this emotional potency can at times be challenging for a modern historian to decipher and explain. This article will attempt to answer some of these questions and suggest some of the skills we as historians need to develop in order to appreciate the full meaning of songs as the most popular of news media in early modern Europe

Multifunctional, self-assembling, anionic peptide-lipid nanocomplexes for targeted siRNA delivery

Formulations of cationic liposomes and polymers readily self-assemble by electrostatic interactions with siRNA to form cationic nanoparticles which achieve efficient transfection and silencing in vitro. However, the utility of cationic formulations in vivo is limited due to rapid clearance from the circulation, due to their association with serum proteins, as well as systemic and cellular toxicity. These problems may be overcome with anionic formulations but they provide challenges of self-assembly and transfection efficiency. We have developed anionic, siRNA nanocomplexes utilizing anionic PEGylated liposomes and cationic targeting peptides that overcome these problems. Biophysical measurements indicated that at optimal ratios of components, anionic PEGylated nanocomplexes formed spherical particles and that, unlike cationic nanocomplexes, were resistant to aggregation in the presence of serum, and achieved significant gene silencing although their non-PEGylated anionic counterparts were less efficient. We have evaluated the utility of anionic nanoparticles for the treatment of neuronal diseases by administration to rat brains of siRNA to BACE1, a key enzyme involved in the formation of amyloid plaques. Silencing of BACE1 was achieved in vivo following a single injection of anionic nanoparticles by convection enhanced delivery and specificity of RNA interference verified by 5' RACE-PCR and Western blot analysis of protein

PEGylation improves the receptor-mediated transfection efficiency of peptide-targeted, self-assembling, anionic nanocomplexes

Non-viral vector formulations comprise typically complexes of nucleic acids with cationic polymers or lipids. However, for in vivo applications cationic formulations suffer from problems of poor tissue penetration, non-specific binding to cells, interaction with serum proteins and cell adhesion molecules and can lead to inflammatory responses. Anionic formulations may provide a solution to these problems but they have not been developed to the same extent as cationic formulations due to difficulties of nucleic acid packaging and poor transfection efficiency. We have developed novel PEGylated, anionic nanocomplexes containing cationic targeting peptides that act as a bridge between PEGylated anionic liposomes and plasmid DNA. At optimized ratios, the components self-assemble into anionic nanocomplexes with a high packaging efficiency of plasmid DNA. Anionic PEGylated nanocomplexes were resistant to aggregation in serum and transfected cells with a far higher degree of receptor-targeted specificity than their homologous non-PEGylated anionic and cationic counterparts. Gadolinium-labeled, anionic nanoparticles, administered directly to the brain by convection-enhanced delivery displayed improved tissue penetration and dispersal as well as more widespread cellular transfection than cationic formulations. Anionic PEGylated nanocomplexes have widespread potential for in vivo gene therapy due to their targeted transfection efficiency and ability to penetrate tissues

Preface

[No abstract available

outrage de la censure à la mémoire de Manuel.

OPLADEN-RUG0

Active Views for Electronic Commerce

Electronic commerce is emerging as a major Web-supported application. In this paper we argue that database technology can, and should, provide the backbone for a wide range of such applications. More precisely, we present here the ActiveViews system, which, relaying on an extensive use of database features including views, active rules (triggers), and enhanced mechanisms for notification, access control and logging/tracing of users activities, provides the needed basis for electronic commerce. Based o