Poly(vinyl alcohol)s and Their Glycoderivatives as Efficient Shell-Builders of Nanocapsules by Nanoprecipitation.

Poly(vinyl alcohol)s (PVAs) are very popular dispersants for the construction of colloids and common shell-constituents of microcapsules but remain mostly unexplored as building blocks for the design of nanocapsules through nanoprecipitation or other processes. Herein, we first show that model commercial PVAs and oils can be concomitantly engaged in solvent-shifting procedures to give rise to oil-filled nanocapsules in one step. Next, we report the synthesis of precisely defined water-soluble glyco-PVAs by reversible addition-fragmentation chain transfer (RAFT) copolymerization of 6-O-vinyladipoyl-d-glucopyranose and vinyl chloroacetate and selective alcoholysis reactions. We finally demonstrate that these glycopolymers are excellent candidates for the straightforward conception of oil- and drug-filled, surface- and/or core-tagged, stealth, and degradable nanocapsules by nanoprecipitation.

Fructose/glycerol/water as a biosourced LTTM solvent to design a variety of sodium alginate-based soft materials with enhanced rheological properties.

Sodium alginate was associated to a ternary solvent composed of fructose, glycerol, and water in a 1:1:5 M ratio (FGW), classified as a natural Low Transition Temperature Mixture (LTTM), to generate various soft materials. The rheological properties of mixtures composed of sodium alginate and FGW were thoroughly analyzed and compared to their aqueous analogues. FGW-based solutions present a pronounced shear-thinning character combined to high viscosity, up to 8000 Pa.s. The overlap concentrations and intrinsic viscosities values evidence a good solvent character of FGW for alginate polymer chains. The increase of alginate concentration in FGW leads to materials with enhanced elasticity (up to 6000 Pa) and high energy of activation (55 kJ/mol). Interestingly, the addition of divalent calcium cations in FGW according to two optimized experimental protocols, allows for the generation of never described ionotropic gels in FGW under various shapes as bulk gels or beads of gels able to encapsulate extracted vegetal actives that are used in the cosmetic industry. Thus, FGW appears as a well-suited solvent of alginate to design a broad range of new biobased soft materials.

α-Substituted ketones as reagent for Passerini modification of carboxymethyl cellulose: Toward dually functionalized derivatives and thermo-sensitive chemical hydrogels.

The present works describes the Passerini modification of carboxymethyl cellulose (CMC) by using a library of nine α-substituted ketones derivatives, differing in their hydrophobicity and reactivity, conjointly with cyclohexyl isocyanide. The Passerini ligation, achieved in aqueous and mild conditions, was shown to be successful, leading to a large panel of dually functionalized CMC derivatives, in an eco-friendly manner. A particular attention was dedicated to the influence of the experimental parameters such as the stoichiometry, the nature of a co-solvent or the temperature, which allowed to tune the extent of modification. The reactivity of the ketone was proven to be governed by its i) compatibility with water, ii) sterical accessibility, and by iii) the presence of neighboring electron-withdrawing group. The resulting Passerini CMC products modified by methacrylate moieties (CMC-MA) were used as reactive macromonomer under a "grafting through" approach. The copolymerization of CMC-MA with oligoethylene glycol methacrylate (OEGMA) and diethylene glycol methacrylate (DEGMA) upon thermal radical reaction conditions enabled to generate tightly cross-linked chemical hydrogels, with a thermo-sensitive and thermo-reversible behavior, reflected by a macroscopical shrinkage/swelling response, and confirmed by SAXS analysis. Such chemical strategy paves the way toward multifunctional polysaccharide-based networks with potential utilizations as drug delivery devices, dye removals or actuators.

Fluorescent Polymer-AS1411-Aptamer Probe for dSTORM Super-Resolution Imaging of Endogenous Nucleolin.

Nucleolin is a multifunctional protein involved in essential biological processes. To precisely localize it and unravel its different roles in cells, fluorescence imaging is a powerful tool, especially super-resolution techniques. Here, we developed polymer-aptamer probes, both small and bright, adapted to direct stochastic optical reconstruction microscopy (dSTORM). Well-defined fluorescent polymer chains bearing fluorophores (AlexaFluor647) and a reactive end group were prepared via RAFT polymerization. The reactive end-group was then used for the oriented conjugation with AS1411, a DNA aptamer that recognizes nucleolin with high affinity. Conjugation via strain-promoted alkyne/azide click chemistry (SPAAC) between dibenzylcyclooctyne-ended fluorescent polymer chains and 3'-azido-functionalized nucleic acids proved to be the most efficient approach. In vitro and in cellulo evaluations demonstrated that selective recognition for nucleolin was retained. Their brightness and small size make these polymer-aptamer probes an appealing alternative to immunofluorescence, especially for super-resolution (10-20 nm) nanoscopy. dSTORM imaging demonstrated the ability of our fluorescent polymer-aptamer probe to provide selective and super-resolved detection of cell surface nucleolin.

Zwitterionic Silicone Materials Derived from Aza-Michael Reaction of Amino-Functional PDMS with Acrylic Acid.

Supramolecular zwitterionic silicones are synthesized by aza-Michael reaction between acrylic acid and amine-functional polydimethylsiloxanes. The in-depth characterization of this chemistry, applied for the first time to silicones, is investigated first with model alkylamines (hexylamine, 2-ethylhexylamine and N-propylethylenediamine), a model oligosiloxane (3-aminopropylmethyl bis(trimethylsiloxy)silane), and finally various amino-polysiloxanes. It is shown that after a first acid-base reaction resulting in ionic pairing, aza-Michael addition proceeds smoothly in mild conditions (50 °C, 1-week reaction). Both monoadducts and di-adducts, together with residual amine, are observed by NMR. The supramolecular assembly of the thus-created zwitterionic moieties is highlighted by a concomitant increase in viscosity and phase separation, as observed by transmission electron microscopy, bringing an additional glass transition at -40 °C assigned to highly polar ionic clusters. Below the stoichiometry in acrylic acid, all zwitterionic silicones follow the same classical behavior of nonentangled polymers according to the Rouse model, whereas upon introducing an excess of acrylic acid to amino groups, an enhancement of the elasticity is observed. Finally, silicone elastomers with solid-like behavior and elastomeric mechanical properties are obtained using a high molar mass polymer bearing bifunctional N-(2-aminoethyl)-3-aminopropyl units that favor a high degree of physical crosslinking.

Solvent-Free Synthesis of Amidated Carboxymethyl Cellulose Derivatives: Effect on the Thermal Properties.

The present work explores the possibility of chemically modifying carboxymethyl cellulose (CMC), a widely diffused commercial cellulose ether, by grafting of hydrophobic moieties. Amidation of CMC, at high temperature and in heterogeneous conditions, was selected as synthetic tool for grafting on CMC a panel of commercially available amines (bearing long aliphatic chains, alkyl aromatic and heteroaromatic groups, more or less spaced from the cellulose backbone). The reaction was successfully carried out in absence of solvents, catalysts and coupling agents, providing a promising and more sustainable alternative to conventional amidation procedures. Relationships between the chemical structure of the obtained CMC derivatives and their thermal properties were carefully studied, with a particular attention to the thermal behavior. Grafting of aromatic and heteroaromatic alkyl amines, presenting a linear alkyl chain between CMC backbone and a terminal bulky moiety, allowed for efficiently separating the polysaccharide chains, improving their mobility and resulting in a consequent lowering of the glass transition temperature (Tg). The Tg values obtained (90-147 °C) were found to be closely dependent on both the size of the aliphatic spacer, the structure of the aromatic ring and the extent of amidation.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide.

A strategy for the assembly of the entire carbon backbone of a stereoisomer of the antitumor marine natural product hemicalide has been investigated. The devised convergent approach relies on Horner-Wadsworth-Emmons and Julia-Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 double bonds, respectively, an aldol reaction to create the C27-C28 bond, and a Suzuki-Miyaura cross-coupling as the endgame to form the C15-C16 bond.

Homogeneous acylation of Cellulose diacetate: Towards bioplastics with tuneable thermal and water transport properties.

In this study, we report a simple, non-degrading and efficient homogeneous acylation of cellulose diacetate (CDA) by using a large panel of commercially available acylating aliphatic moieties, differing in their structure (fatty, ramified, bulky, cycloaliphatic, aromatic, more or less spaced from the cellulose backbone), in view of generating a library of well-defined cellulose mixed esters with enhanced thermoplasticity. As reflected by a lowering of the glass temperature (Tg), the covalent grafting confers an improved mobility to the cellulose chains, by disrupting the initial H-bonds. In particular, it appears that the gain in free volume is tailored by the substituent structure and that acylating reagents consisting in a terminal bulky moieties spaced from CDA chains by a linear chain efficiently separate macromolecular chains without generating detrimental stiffening interactions (low Tg around 125 °C). Moreover, free-standing films easily prepared by solvent casting exhibit relevant water transport properties, which are closely dictated and tuned by the water solubility of the cellulose mixed ester.

Biohybrid cellulose fibers: Toward paper materials with wet strength properties.

Herein, we report on the preparation of novel cellulose-PEG biohybrid papers with wet strength properties. The biohybrid paper sheets are obtained using a two-step procedure where ω- or α, ω-azide functionalized PEG chains are anchored onto alkyne-functionalized wood fibers through CuAAC ligation in mild and aqueous conditions. The incorporation of the PEG grafts mostly occurs at the periphery of the cellulose fibers and degrees of substitution up to 0.028 are obtained. The presence of PEG grafts significantly increases the tensile, burst and tear strength properties in the wet state, the reinforcement being more pronounced for fibers grafted with α,ω-azide PEG. This reinforcement is consistent with a relatively sparse hetero-crosslink reaction creating inter-fiber covalent bonds and forming a cellulose network within the cell wall.

Guar gum as biosourced building block to generate highly conductive and elastic ionogels with poly(ionic liquid) and ionic liquid.

In this study, we report on the simple and straightforward preparation of ionogels arising from the addition of guar gum (a plant-based polysaccharide) in a solution of precisely-defined poly(ionic liquid) chains (PIL) in imidazolium-based ionic liquid (IL). The development of intermolecular polar interactions (mainly hydrogen bonds) and topologic chain entanglements induces the formation of physical biohybrid ionogels, whose elastic properties can be easily tuned by varying the composition (up to 30000Pa). The combined presence of guar gum and PIL confers excellent dimensional stability to the ionogels with no IL exudation combined with high thermal properties (up to 310°C). The resulting materials are shown to exhibit gel scattering profiles and high conductivities (> 10-4S/cm at 30°C). The benefit linked to the formation of guar/PIL associations in IL medium enables to find a good compromise between the mechanical cohesion and the mobility ensuring the ionic transport.

Sweet supramolecular elastomers from α,ω-(ß-cyclodextrin terminated) PDMS.

Azido ß-cyclodextrins were attached to propiolate-functionalized polydimethylsiloxanes by metal-free click chemistry. The obtained telechelic copolymers spontaneously produced elastomeric gums. Demixing and supramolecular associations are the driving forces for the construction of these strongly associated (but reversible) physical networks.

Development of Heptylmannoside-Based Glycoconjugate Antiadhesive Compounds against Adherent-Invasive Escherichia coli Bacteria Associated with Crohn's Disease.

UNLABELLED: The ileal lesions of Crohn's disease (CD) patients are colonized by adherent-invasive Escherichia coli (AIEC) bacteria. These bacteria adhere to mannose residues expressed by CEACAM6 on host cells in a type 1 pilus-dependent manner. In this study, we investigated different antagonists of FimH, the adhesin of type 1 pili, for their ability to block AIEC adhesion to intestinal epithelial cells (IEC). Monovalent and multivalent derivatives of n-heptyl α-d-mannoside (HM), a nanomolar antagonist of FimH, were tested in vitro in IEC infected with the AIEC LF82 strain and in vivo by oral administration to CEACAM6-expressing mice infected with LF82 bacteria. In vitro, multivalent derivatives were more potent than the monovalent derivatives, with a gain of efficacy superior to their valencies, probably owing to their ability to form bacterial aggregates. Of note, HM and the multi-HM glycoconjugates exhibited lower efficacy in vivo in decreasing LF82 gut colonization. Interestingly, HM analogues functionalized with an isopropylamide (1A-HM) or ß-cyclodextrin pharmacophore at the end of the heptyl tail (1CD-HM) exerted beneficial effects in vivo. These two compounds strongly decreased the amount of LF82 bacteria in the feces of mice and that of bacteria associated with the gut mucosa when administered orally at a dose of 10 mg/kg of body weight after infection. Importantly, signs of colitis and intestinal inflammation induced by LF82 infection were also prevented. These results highlight the potential of the antiadhesive compounds to treat CD patients abnormally colonized by AIEC bacteria and point to an alternative to the current approach focusing on blocking proinflammatory mediators. IMPORTANCE: Current treatments for Crohn's disease (CD), including immunosuppressive agents, anti-tumor necrosis factor alpha (anti-TNF-α) and anti-integrin antibodies, focus on the symptoms but not on the cause of the disease. Adherent-invasive Escherichia coli (AIEC) bacteria abnormally colonize the ileal mucosa of CD patients via the interaction of the mannose-specific adhesin FimH of type 1 pili with CEACAM6 mannosylated proteins expressed on the epithelial cell surface. Thus, we decided to develop an antiadhesive strategy based on synthetic FimH antagonists specifically targeting AIEC bacteria that would decrease intestinal inflammation. Heptylmannoside (HM)-based glycocompounds strongly inhibit AIEC adhesion to intestinal epithelial cells in vitro. The antiadhesive effect of two of these compounds of relatively simple chemical structure was also observed in vivo in AIEC-infected CEACAM6-expressing mice and was associated with a reduction in the signs of colitis. These results suggest a new therapeutic approach for CD patients colonized by AIEC bacteria, based on the development of synthetic FimH antagonists.

Brilliant glyconanocapsules for trapping of bacteria.

Nanoprecipitation of miglyol into droplets surrounded by a functional glycopolymer generates nanocapsules of biointerest. Fluorophores are trapped in situ or post-grafted onto the crosslinked polymer shell for efficient imaging. The resulting colloids induce aggregation of bacteria through strong specific interactions and promote their facile removal.

Glycopolymers as Antiadhesives of E. coli Strains Inducing Inflammatory Bowel Diseases.

n-Heptyl α-d-mannose (HM) is a nanomolar antagonist of FimH, a virulence factor of E. coli. Herein we report on the construction of multivalent HM-based glycopolymers as potent antiadhesives of type 1 piliated E. coli. We investigate glycopolymer/FimH and glycopolymer/bacteria interactions and show that HM-based glycopolymers efficiently inhibit bacterial adhesion and disrupt established cell-bacteria interactions in vitro at very low concentration (0.1 µM on a mannose unit basis). On a valency-corrected basis, HM-based glycopolymers are, respectively, 10(2) and 10(6) times more potent than HM and d-mannose for their capacity to disrupt the binding of adherent-invasive E. coli to T84 intestinal epithelial cells. Finally, we demonstrate that the antiadhesive capacities of HM-based glycopolymers are preserved ex vivo in the colonic loop of a transgenic mouse model of Crohn's disease. All together, these results underline the promising scope of HM-based macromolecular ligands for the antiadhesive treatment of E. coli induced inflammatory bowel diseases.

Aqueous RAFT Polymerization of Imidazolium-Type Ionic Liquid Monomers: En Route to Poly(ionic liquid)-Based Nanoparticles through RAFT Polymerization-Induced Self-Assembly.

The synthesis by aqueous RAFT polymerization of hydrophilic narrowly dispersed imidazolium-based poly(ionic liquid)s (D typically below 1.20) is reported. Full monomer conversion is achieved within hours and high end-group fidelity of the living end groups affords the preparation of well-defined block copolymers. The resulting poly(ionic liquid) macroRAFT agents are finally exploited to polymerize 2-vinylpyridine in water and generate PIL-based nanoparticles of various morphologies (spheres, vesicles, or worms) in a one-pot surfactant-free process.

Redox-stimuli responsive micelles from DOX-encapsulating polycaprolactone-g-chitosan oligosaccharide.

Chitosan-based amphiphilic graft copolymers are commonly obtained by modification of chitosan backbones with synthetic polymers hampering both bioactivity and biodegradability. In this work, we report the preparation of a series of chitosan oligosaccharide-grafted copolymers (PCL-g-COs) from coupling reactions between azide-pendent polycaprolactones (PCL-N3) and reducing-end alkynyl-modified chitosan oligosaccharides (COs-alkynyl). The resulting PCL-g-COs self-organized in water into nanoscale micelles (Rh<20 nm) having a COs shell and a PCL core. Locking of the core-micelles structure employing a disulfide-containing bis-alkyne cross-linker resulted in the formation of nano-vehicles which can be degraded in response to physiological (redox) stimuli. This feature was advantageously exploited to preferentially release an anticancer drug, doxororubicin, in response to the intracellular glutathione level.

Simple but precise engineering of functional nanocapsules through nanoprecipitation.

A general, rapid, and undemanding method to generate at will functional oil-filled nanocapsules through nanoprecipitation is reported. On the basis of polymer and hexadecane/water/acetone phase diagrams, the composition can be set so that polymer chains preferentially stick at the interface of the oil droplets to create nanocapsules. The nanocapsules can be decorated with biorelevant molecules (biotin, fluorescent tags, metal nanoparticles) within the shell and loaded with hydrophobic molecules in a simple one-pot procedure.

Dual guar/ionic liquid gels and biohybrid material thereof: rheological investigation.

Polysaccharide-based ion gels were prepared by mixing biosourced guar gums with imidazolium ionic liquid (IL) molecules that act as crosslinking agents. The in-depth investigation of the rheological properties of the guar/IL solutions emphasized that the shear viscoelastic properties can be finely tuned by IL chemical structure, concentration and molecular weight of guar chains as well as by temperature changes. Under suited conditions, highly elastic physical ion gels were formed as a result of multiple guar/IL, guar/guar and IL/IL interactions. Such synergistic associations were usefully exploited to elaborate films dually composed of guar chains and entrapped IL molecules. Their thermomechanical properties, which revealed a solid-state behavior, were closely controlled by the structural parameters of the constituents. This straightforward approach, which requires no chemical derivatization step, provides a facile way to design physical gels with a large applicative potential.

Synthetic studies on hemicalide: development of a convergent approach toward the C1-C25 fragment.

Synthetic studies on hemicalide, a recently isolated marine natural product displaying highly potent antiproliferative activity and a unique mode of action, have highlighted a reliable Horner-Wadsworth-Emmons olefination to create the C6-C7 alkene and a remarkable efficient Suzuki-Miyaura coupling to form the C15-C16 bond, resulting in the development of a convergent approach toward the C1-C25 fragment.

Silicone-based surfactant degradation in aqueous media.

The increasing use of surfactants, such as modified polydimethylsiloxane-graft-polyethylene oxide (PDMS-g-PEO), requires studies on the fate of these compounds in the environment, and in particular in wastewater systems. A kinetic study, performed under three different pH conditions (pH2, 5.3 and 11) and using (1)H NMR (Nuclear Magnetic Resonance), proves that hydrolysis of the siloxane chain takes place in all cases, with higher rates for the two extreme conditions. Steric exclusion chromatography (SEC) clearly showed a decrease in the average molecular weight of the copolymer leading to a new molecular weight distribution, especially in acidic conditions. Degradation products, analyzed by (29)Si NMR, were found to be similar whatever the degradation pathway, namely silanediols and cyclic volatile compounds (degradation products of PDMS) and also PEO-modified silanediols and cyclic compounds. After one year, the siloxane chain completely disappeared under acidic conditions. Real wastewater medium has a strong effect on polymer stability, indicating that pH is not the only parameter which influences degradation rate.