Functional polylactide via ring-opening copolymerisation with allyl, benzyl and propargyl glycidyl ethers.

A versatile and simple strategy is presented to synthesize reactive polylactide derivatives and their block copolymers with polyethylene glycol. Commercially available glycidyl ethers with an allyl, benzyl or propargyl functional group were copolymerised with D,L-lactide. Tin(II)-2- ethylhexanoate-catalysis produced polymers with up to 4.6, 5.9 and 2.3 allyl, benzyl or propargyl groups per chain, respectively. In contrast, less than one reactive group per chain was obtained with the organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene. By increasing the polymerisation feed ratio in glycidyl ether polymers with a higher number of reactive groups per chain were obtained, however a decrease in molar mass was observed. An azidocoumarin was conjugated to the propargylated polymers via copper-catalysed azide-alkyne cycloaddition. These dye-labelled polymers produced nanospheres with fluorescent properties and diameters in the 100-nm sizerange, as characterised by asymmetric flow field flow fractionation hyphenated with fluorescence, static and dynamic light scattering detection. The functionalised polymers were obtained at gram-scale in one step from commercially available reagents; therefore providing a robust and easy to implement approach for the production of multifunctional nanomaterials

Ravuconazole self-emulsifying delivery system : in vitro activity against Trypanosoma cruzi amastigotes and in vivo toxicity.

Self-emulsifying drug delivery systems (SEDDSs) are lipid-based anhydrous formulations composed of an isotropic mixture of oil, surfactant, and cosurfactants usually presented in gelatin capsules. Ravuconazole (Biopharmaceutics Classification System [BCS] Class II) is a poorly water-soluble drug, and a SEDDS type IIIA was designed to deliver it in a predissolved state, improving dissolution in gastrointestinal fluids. After emulsification, the droplets had mean hydrodynamic diameters ,250 nm, zeta potential values in the range of -45 mV to -57 mV, and showed no signs of ravuconazole precipitation. Asymmetric flow field-flow fractionation with dynamic and multiangle laser light scattering was used to characterize these formulations in terms of size distribution and homogeneity. The fractograms obtained at 37?C showed a polydisperse profile for all blank and ravuconazole?SEDDS formulations but no large aggregates. SEDDS increased ravuconazole in vitro dissolution extent and rate (20%) compared to free drug (3%) in 6 h. The in vivo toxicity of blank SEDDS comprising Labrasol? surfactant in different concentrations and preliminary safety tests in repeated-dose oral administration (20 days) showed a dose-dependent Labrasol toxicity in healthy mice. Ravuconazole?SEDDS at low surfactant content (10%, v/v) in Trypanosoma cruzi-infected mice was safe during the 20-day treatment. The anti-T. cruzi activity of free ravuconazole, ravuconazole?SEDDS and each excipient were evaluated in vitro at equivalent ravuconazole concentrations needed to inhibit 50% or 90% (IC50 and IC90), respectively of the intracellular amastigote form of the parasite in a cardiomyocyte cell line. The results showed a clear improvement of the ravuconazole anti-T. cruzi activity when associated with SEDDS. Based on our results, the repurposing of ravuconazole in SEDDS dosage form is a strategy that deserves further in vivo investigation in preclinical studies for the treatment of human T. cruzi infections

Lithographically Defined Cross-Linkable Top Coats for Nanomanufacturing with High-χ Block Copolymers

The directed self-assembly (DSA) of block copolymers (BCPs) is a powerful method for the manufacture of high-resolution features. Critical issues remain to be addressed for successful implementation of DSA, such as dewetting and controlled orientation of BCP domains through physicochemical manipulations at the BCP interfaces, and the spatial positioning and registration of the BCP features. Here, we introduce novel top-coat (TC) materials designed to undergo cross-linking reactions triggered by thermal or photoactivation processes. The cross-linked TC layer with adjusted composition induces a mechanical confinement of the BCP layer, suppressing its dewetting while promoting perpendicular orientation of BCP domains. The selection of areas of interest with perpendicular features is performed directly on the patternable TC layer via a lithography step and leverages attractive integration pathways for the generation of locally controlled BCP patterns and nanostructured BCP multilayers

Impact of dose and surface features on plasmatic and liver concentrations of biodegradable polymeric nanocapsules.

The effect of polymeric nanocapsule dose on plasmatic and liver concentrations 20 min after intravenous administration in mice was evaluated. Nanocapsules were prepared with different polymers, namely, poly(D,Llactide) (PLA), polyethylene glycol-block-poly(D,L-lactide) (PLA-PEG), and PLA with chitosan (PLA-Cs) and compared with a nanoemulsion. These formulations were labelled with a phthalocyanine dye for fluorescent detection. The nanostructures had narrow size distributions upon separation by asymmetric flow field flow fractionation with static and dynamic light scattering detection, with average hydrodynamic diameters in the 130?300 nm range, negative zeta potentials, except PLA-Cs nanocapsules, which had a positive zeta potential. Flow cytometry revealed uptake mostly by monocytes and neutrophils in mice and human blood. PLA nanocapsules and the nanoemulsion showed dose-dependent plasma concentrations, where the percentage of plasmatic fluorescence increased with increasing administered dose. In contrast, PLA-PEG nanocapsules led to a dose-independent plasmatic profile. PLA-Cs nanocapsules showed the lowest plasmatic and liver levels of fluorescence at all administered doses and significant intravenous toxicity in mice. This work demonstrates the importance of considering the nanocarrier dose when evaluating pharmacokinetic and biodistribution data and emphasizes the role of surface features in determining the plasmatic and liver concentrations of a poorly soluble lipophilic encapsulated compound

Reversible addition fragmentation chain transfer (RAFT) mediated polymerization of N-vinylpyrrolidone

Thesis (PhD (Chemistry and Polymer Science)--University of Stellenbosch, 2008.Xanthate-mediated polymerization was investigated as a tool for the preparation of well-defined poly(N-vinylpyrrolidone) and copolymers of N-vinylpyrrolidone. Some results regarding the monomer vinyl acetate are included, mostly for comparison purposes. The structure of the leaving/reinitiating group of the xanthate mediating agent was tuned to match the monomer reactivity. This was achieved by studying the initialization behaviour of monomer-xanthate systems via in situ 1H-NMR spectroscopy. Additionally, the latter technique was valuable to identify side reactions affecting the monomer, xanthate and/or polymeric species. Subsequently, experimental conditions were defined, and used to optimize the level of control achieved during polymerization. Block copolymers were prepared from a xanthate end-functional poly(ethylene glycol) with both vinyl acetate and N-vinylpyrrolidone. Finally, the preparation of poly(N-vinylpyrrolidone) with a range of well-defined end groups was achieved via postpolymerization treatment of the xanthate end-functional polymerization product. 3 different routes were investigated, which lead to poly(N-vinylpyrrolidone) with 1) aldehyde or alcohol, 2) thiol or 3) unsaturated ω-chain-end functionality, in high yield, while the α-chain-end functionality is defined by the structure of the xanthate leaving group. The ω-aldehyde end-functional poly(N-vinylpyrrolidone) was successfully conjugated to the lysine residues of the model protein lysozyme via reductive amination. Particular attention was drawn to characterizing the polymerization products. NMR spectroscopy, liquid chromatographic and mass-spectroscopic techniques were used. The major achievements emerging from polymer analysis carried out in this study included the following: - a library of NMR chemical shifts for N-vinylpyrrolidone derivatives; - an estimation of the critical conditions for poly(N-vinylpyrrolidone) relevant for separation according to the polymer chain-ends; - conditions for the separation of block-copolymers comprising a poly(ethylene glycol) segment and a poly(N-vinylpyrrolidone) or poly(vinyl acetate) segment via liquid chromatography; - valuable results on matrix-assisted laser ionization-desorption time-of-flight mass spectroscopy (MALDI-ToF-MS) of poly(N-vinylpyrrolidone)

Dry-Etching Processes for High-Aspect-Ratio Features with Sub-10 nm Resolution High-χ Block Copolymers

International audienceDirected self-assembly of block copolymers (BCP) is a very attractive technique for the realization of functional nanostructures at high resolution. In this work, we developed full dry-etching strategies for BCP nanolithography using an 18 nm pitch lamellar silicon-containing block copolymer. Both an oxidizing Ar/O2 plasma and a nonoxidizing H2/N2 plasma are used to remove the topcoat material of our BCP stack and reveal the perpendicular lamellae. Under Ar/O2 plasma, an interfacial layer stops the etch process at the topcoat/BCP interface, which provides an etch-stop but also requires an additional CF4-based breakthrough plasma for further etching. This interfacial layer is not present in H2/N2. Increasing the H2/N2 ratio leads to more profound modifications of the silicon-containing lamellae, for which a chemistry in He/N2/O2 rather than Ar/O2 plasma produces a smoother and more regular lithographic mask. Finally, these features are successfully transferred into silicon, silicon-on-insulator, and silicon nitride substrates. This work highlights the performance of a silicon-containing block copolymer at 18 nm pitch to pattern relevant hard-mask materials for various applications, including microelectronics

Self-organization and dewetting kinetics in sub-10 nm diblock copolymer line/space lithography

International audienceIn this work, we investigated the self-assembly of a lamellar block copolymer (BCP) under different wetting conditions. We explored the influence of the chemical composition of under-layers and top-coats on the thin film stability, self-assembly kinetics and BCP domain orientation. Three different chemistries were chosen for these surface affinity modifiers and their composition was tuned in order to provide either neutral wetting (i.e. an out-of-plane lamellar structure), or affine wetting conditions (i.e. an in-plane lamellar structure) with respect to a sub-10 nm PS- b -PDMSB lamellar system. Using such controlled wetting configurations, the competition between the dewetting of the BCP layer and the self-organization kinetics was explored. We also evaluated the spreading parameter of the BCP films with respect to the configurations of surface-energy modifiers and demonstrated that BCP layers are intrinsically unstable to dewetting in a neutral configuration. Finally, the dewetting mechanisms were evaluated with respect to the different wetting configurations and we clearly observed that the rigidity of the top-coat is a key factor to delay BCP film instability

Phthalocyanine photosensitizer in polyethylene glycol-block-poly(lactide-co-benzyl glycidyl ether) nanocarriers: Probing the contribution of aromatic donor-acceptor interactions in polymeric nanospheres

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An Ultra-Thin Near-Perfect Absorber via Block Copolymer Engineered Metasurfaces

International audienceProducing ultrathin light absorber layers is attractive towards the integration of lightweight planar components in electronic, photonic, and sensor devices. In this work, we report the experimental demonstration of a thin gold (Au) metallic metasurface with near-perfect visible absorption (~ 95 %). Au nanoresonators possessing heights from 5-15 nm with sub-50 nm diameters were engineered by block copolymer (BCP) templating. The Au nanoresonators were fabricated on an alumina (Al2O3) spacer layer and a reflecting Au mirror, in a film-coupled nanoparticle design. The BCP nanopatterning strategy to produce desired heights of Au nanoresonators was tailored to achieve nearperfect absorption at ≈ 600 nm. The experimental insight described in this work is a step forward towards realizing large area flat optics applications derived from subwavelengththin metasurfaces