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.

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.

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.

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.

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.

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.

Aniline-catalyzed reductive amination as a powerful method for the preparation of reducing end-"clickable" chitooligosaccharides.

Functionalized oligosaccharides are useful intermediates to prepare products for biological research or for the development of advanced functional materials. Here, we report the unprecedented use of aniline as an efficient organocatalyst reaction with "clickable" (azide or alkyne) amine for the transimination-mediated reductive amination of a chitooligosaccharide. Moreover, we demonstrate that alkyne-bearing aniline constitutes an excellent tool for the easy derivatization of chitosan oligosaccharides. Evidence for such improvement has been illustrated by the straightforward design of a FRET substrate to probe chitinase activity and of amphiphilic polycaprolactone-grafted-chitosan. This efficient methodology paves the way to the preparation of novel chitosan oligosaccharide-based advanced materials.

Green nondegrading approach to alkyne-functionalized cellulose fibers and biohybrids thereof: synthesis and mapping of the derivatization.

Alkyne-functionalized cellulose fibers have been generated through etherification under basic water or hydroalcoholic conditions (NaOH/H(2)O/isopropanol). For a given NaOH content, the medium of reaction and, more particularly, the water/IPA ratio, were shown to be of crucial importance to derivatize the fibers without altering their integrity and their crystalline nature. It was shown that the degree of substitution (DS) of the fibers increases concomitantly with isopropanol weight ratio and that, contrary to water or water-rich conditions, derivatization of fibers under isopropanol-rich conditions induces an alteration of the fibers. Optimization of etherification conditions in aqueous media afforded functionalized cellulose materials with DS up to 0.20. Raman confocal microscopy on derivatized fibers cross sections stressed that alkyne moieties are incorporated all over the fibers. The resulting fibers were postfunctionalized by molecular probes and macromolecules in aqueous or water-rich conditions. The effectiveness of the grafting was strongly impacted by the nature of the coupling agents.

Relative stereochemical determination and synthesis of the C17-C25 δ-lactone fragment of hemicalide.

Hemicalide is a novel marine metabolite polyketide distinguished by a unique mechanism of action. Because of insufficient quantities of purified material, this natural product has evaded complete stereochemical assignments. Recently, we have determined the relative stereochemistry of the C8-C13 hexad by synthesizing the C1-C13 fragment. Presently, we report the assignment of the C17-C25 δ-lactone fragment. NMR analysis of authentic hemicalide along with a computational conformation study allowed us to reduce the number of putative relative isomers from 16 to 4. Concise syntheses of the four candidate diastereomers were achieved using a common strategy based on a Dias aldehyde allylation reaction, an intramolecular Horner-Wadsworth-Emmons olefination, and a dihydroxylation reaction. Finally, thorough NMR comparisons enabled us to deduce the relative stereochemistry of the C1-C17 fragment with high certainty.

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.

Structure-properties relationship of biosourced stereocontrolled polytriazoles from click chemistry step growth polymerization of diazide and dialkyne dianhydrohexitols.

The design of dialkyne and diazide functionalized dianhydrohexitol stereoisomers (1-6) afforded a new family of starch-based polytriazoles (7-15) with defined stereochemistry through A(2) + B(2) CuAAC step growth polymerization. The present strategy gave rise to polytriazoles having a high biosourced weight fraction (superior to 60% wt) and exhibiting relatively high molar masses (M(n) = 8-17 kg/mol) that could be easily dissolved in DMF or DMSO. The obtained materials were amorphous and displayed high transition temperatures (T(g) = 125-166 °C) as well as good resistance to thermal degradation (T(d10) = 325-347 °C). Monomer stereochemistry proved to be a crucial parameter aiming at generating polymers with high T(g). Thus, optimal thermal properties were obtained with monomers having RR absolute configuration of the C-2 and C-5 carbon atoms (isomannide configuration).

Modification of polysaccharides through controlled/living radical polymerization grafting-towards the generation of high performance hybrids.

This review covers the literature concerning the modification of polysaccharides through controlled radical polymerizations (NMP, ATRP and RAFT). The different routes to well-defined polysaccharide-based macromolecules (block and graft copolymers) and graft-functionalized polysaccharide surfaces as well as the applications of these polysaccharide-based hybrids are extensively discussed.

Relative stereochemical determination and synthesis of the C1-C17 fragment of a new natural polyketide.

The challenging determination of the relative stereochemistry of a complex natural polyketide portion was achieved. After careful NMR analysis, a concise synthesis of a set of possible relative diastereomers (only 6 diastereomers out of the 32 initially envisioned) has been carried out using a common strategy based on enantioselective aldol reactions. With a high predictability, final NMR comparison established the relative stereochemistry of the C1-C17 fragment of this natural product.

The discovery and optimisation of benzazepine sulfonamide and sulfones as potent agonists of the motilin receptor.

Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.

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.

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.

Click chemistry step growth polymerization of novel alpha-azide-omega-alkyne monomers.

A novel step growth polymerization A-B strategy based on the click chemistry polyaddition of tailor-made alpha-azide-omega-alkyne low molar mass monomers was developed, leading to polytriazole (co)polymers with tunable structures and properties.

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.