Functional Graphene for Peritumoral Brain Microenvironment Modulation Therapy in Glioblastoma

Peritumoral brain invasion is the main target to cure glioblastoma. Chemoradiotherapy and targeted therapies fail to combat peritumoral relapse. Brain inaccessibility and tumor heterogeneity explain this failure, combined with overlooking the peritumor microenvironment. Reduce graphene oxide (rGO) provides a unique opportunity to modulate the local brain microenvironment. Multimodal graphene impacts are reported on glioblastoma cells in vitro but fail when translated in vivo because of low diffusion. This issue is solved by developing a new rGO formulation involving ultramixing during the functionalization with polyethyleneimine (PEI) leading to the formation of highly water-stable rGO-PEI. Wide mice brain diffusion and biocompatibility are demonstrated. Using an invasive GL261 model, an anti-invasive effect is observed. A major unexpected modification of the peritumoral area is also observed with the neutralization of gliosis. In vitro, mechanistic investigations are performed using primary astrocytes and cytokine array. The result suggests that direct contact of rGO-PEI_UT neutralizes astrogliosis, decreasing several proinflammatory cytokines that would explain a bystander tumor anti-invasive effect. rGO also significantly downregulates several proinvasive/protumoral cytokines at the tumor cell level. The results open the way to a new microenvironment anti-invasive nanotherapy using a new graphene nanomaterial that is optimized for in vivo brain delivery.     

Targeting the Central Pocket of the Pseudomonas aeruginosa Lectin LecA

Pseudomonas aeruginosa is an opportunistic ESKAPE pathogen that produces two lectins, LecA and LecB, as part of its large arsenal of virulence factors. Both carbohydrate-binding proteins are central to the initial and later persistent infection processes, i. e. bacterial adhesion and biofilm formation. The biofilm matrix is a major resistance determinant and protects the bacteria against external threats such as the host immune system or antibiotic treatment. Therefore, the development of drugs against the P. aeruginosa biofilm is of particular interest to restore efficacy of antimicrobials. Carbohydrate-based inhibitors for LecA and LecB were previously shown to efficiently reduce biofilm formations. Here, we report a new approach for inhibiting LecA with synthetic molecules bridging the established carbohydrate-binding site and a central cavity located between two LecA protomers of the lectin tetramer. Inspired by in silico design, we synthesized various galactosidic LecA inhibitors with aromatic moieties targeting this central pocket. These compounds reached low micromolar affinities, validated in different biophysical assays. Finally, X-ray diffraction analysis revealed the interactions of this compound class with LecA. This new mode of action paves the way to a novel route towards inhibition of P. aeruginosa biofilms.     

Customizable and Reconfigurable Surface Properties of Printed Micro-objects by 3D Direct Laser Writing via Nitroxide Mediated Photopolymerization

Photoactivated Reversible Deactivation Radical Polymerization (RDRP) technologies have emerged very recently in the field of 3D printing systems especially at the macroscale in vat-photopolymerization-based processes such as digital light processing (DLP). Contrary to conventional free radical photopolymerization, photoRDRP in 3D printing leads to 3D objects with living character and thus confers them the unique ability to be post-modified after fabrication. While 3D direct laser writing (3D DLW) by two photon polymerization has become a standard for fabrication of complex 3D micro-objects, the use of RDRP and its associated benefits has so far been under-investigated at that scale. Herein, a photoresist suitable for 3D DLW based on nitroxide mediated photopolymerization (NMP2) is developed. The photopolymerization efficiency for fabrication of micro-structures and their subsequent post-modification are investigated regarding the laser power and the wavelength of excitation. Moreover, highly tunable, precise, and successive surface patterning of 2D and 3D multi-material microstructures are demonstrated thanks to the spatial and temporal control offered by the photo-induced post-modification. This work highlights new directions to be explored in order to accelerate the adoption of RDRP in 3D printing based on photopolymerization.     

Workflow for computational fluid dynamics modeling of fixed-bed reactors packed with metal foam pellets: Hydrodynamics

In recent years, the catalyst pellets made of open-cell metallic foams have been identified as a promising alternative in fixed-bed reactors. A reliable modeling tool is necessary to investigate the suitability of different foam properties and the shapes of foam pellets. In this article, a workflow for a detailed computational fluid dynamics (CFD) model is presented, which aims to study the flow characteristics in the slender packed beds made of metal foam pellets. The CFD model accounts for the actual random packing structure and the fluid flow throughout the interstitial regions is fully resolved, whereas flow through the porous foam pellets is represented by the closure equations for the porous media model. The bed structure is generated using rigid body dynamics (RBD) and the influence of the catalyst loading method is also considered. The mean bed voidage and the pressure drop predicted by the simulations show good agreement with the experimental data.     

Lysosomes Targeting pH Activable Imaging-Guided Photodynamic Agents

Photodynamic therapy (PDT) is a photochemistry-based medical treatment combining light at a specific wavelength and a photosensitizer (PS) in the presence of oxygen. Application of PDT as a conventional treatment is limited and clearly the approval in clinics of new PS is challenging. The selective accumulation of the PS in the targeted malignant cells is of paramount importance to reduce the side effects that are typical of the current worldwide approved PS. Here we report a new series of aniline- and iodine-substituted BODIPY derivatives ( 1 – 3 ) as promising lysosome-targeting and pH-responsive theranostic PS, which displayed a significant in vitro light-induced cytotoxicity, efficient imaging properties and low dark toxicity (for 2 and 3 ). These compounds were obtained in few reproducible synthetic steps and good yields. Spectroscopic and electrochemical measurements along with computational calculations confirmed the quenching of the emissive properties of the PS, while both fluorescence and ¹O₂ emission were obtained only under acidic conditions inducing amine protonation. The pK_a values and pH-dependent emissive properties of 1 – 3 being established, their cellular uptake and activation in the lysosomal vesicles (pH≈4-5) were confirmed by their co-localization with the commercial LysoTracker deep red and light-induced cytotoxicity (IC₅₀ between 0.16 and 0.06 μM) against HeLa cancer cells.     

Hydrogeomorphological processes and plant invasion. What interactions in the case of Asian knotweeds along the Herault River (France)?

Considered one of the five major threats to biodiversity worldwide, Invasive Alien Species (IAS) particularly threaten riparian ecosystems. Among the IAS found on riverbanks, Asian knotweeds (Reynoutria spp. including R. japonica Houtt.; R. sachalinensis [F.Schmidt] Nakai and the hybrid R. x bohemica Chrtek & Chrtkova) can barely be controlled as, once established, they disperse easily along stream banks via rhizome or stem fragments transported by water. However, the hydrogeomorphological processes underlying the establishment of Asian knotweeds are poorly understood. The objective of this study was to describe and model the hydrogeomorphological preferences of Asian knotweeds along a Mediterranean river. Based on exhaustive presence/absence surveys, we implemented two models related to the presence of Asian knotweeds: (1) at the river reach scale and (2) at the finer scale of the alluvial bar. Areas of low curvature identified as convex banks and the central parts of alluvial bars appear to be more susceptible to knotweed establishment. Highly disturbed areas were less favorable to maintaining plant species, including Asian knotweeds, while less disturbed areas with denser plant cover were more favorable to Asian knotweeds. The results seem to indicate a trade-off hypothesis in the knotweed establishment strategy between hydrogeomorphological constraints and strong interspecific competition. Analyzed in the light of the current literature, our final models are designed to integrate hydrogeomorphological processes in order to provide an operational tool to help river managers locate the areas most susceptible to knotweed invasion and with important implications for managing these species in riparian ecosystems.     

Synthesis of N-acetylmuramic acid derivatives as potential inhibitors of the D-glutamic acid-adding enzyme

Compounds containing N-acetyl-D-muramic acid and (L-1-aminoethyl)phosphonic acid were designed as potential inhibitors of the D-glutamic acid-adding enzyme of the biosynthesis of bacterial peptidoglycan. 2-Acetamido-2-deoxy-3-O-[(R)-2-propionyl-(L-1-aminoethyl)phosphonic acid]-D-glucopyranose ( 3 ) was synthesized. 2-Acetamido-1,4,6-tri-O-acetyl-2-deoxy-3-O[(R)-2-propionyl-(L-1-aminoethyl)phosphonic acid dimethyl ester]-α,β-D-glucopyranose ( 9 ) was also prepared and was submitted to the MacDonald reaction in order to introduce a phosphate group on the anomeric position. A complex mixture of phosphorylated or/and methylated derivatives of 3 was obtained. They were purified by h.p.l.c. and characterized by analyses of hexosamine, amino acid and labile phosphate, and by plasma desorption mass spectrometry. Neither 3 nor its derivatives inhibited the D-glutamic acid-adding enzyme from Escherichia coli.     

Synthesis,Catalytic Activity in Oxidation Reactions,and Recyclability of Stable Polyoxometalate‐Centred Dendrimers

Nine‐ and 27‐armed dendrimers with a peroxophosphotungstate core were synthesized by an ionic‐bonding approach and used as air‐stable, recoverable catalysts for oxidation reactions using hydrogen peroxide.