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

The effect of Z-group modification on the RAFT polymerization of N-vinylpyrrolidone controlled by "switchable" N-pyridyl-functional dithiocarbamates

This is an accepted manuscript of an article published by Royal Society of Chemistry in the Polymer Chemistry on 24/08/2015, available online: https://doi.org/10.1039/C5PY01021G The accepted version of the publication may differ from the final published version.The ability of a RAFT agent to control the polymerization of a monomer is dictated by the structures of both the monomer and the RAFT agent. In this paper, the polymerization of N-vinylpyrrolidone was examined with a series of cyanomethyl N-aryl-N-pyridyldithiocarbamates [(4-R′Ph)N(py)C(S)SCH2CN] varying in the substituent (R′) at the 4-position on the phenyl ring. The polymerization of N-vinylpyrrolidone was best controlled when R′ was methoxy; one of the least active RAFT agents in the series. The preservation of RAFT agent functionality was demonstrated by chain extension experiments with further N-vinylpyrrolidone. Again best control again was found for the RAFT agent with R′ = MeOPh. The utility of this RAFT agent was also proved with the preparation of poly(N-isopropylacrylamide)-block-poly(N-vinylpyrrolidone).The authors gratefully acknowledge the Australian Government for award of an Australian Postgraduate Award to S.J.S., the CSIRO Manufacturing Flagship and the School of Science and Technology at the University of New England for project funding.Published versio

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

End-group ionisation enables the use of poly(N-(2-methacryloyloxy)ethyl pyrrolidone) as an electrosteric stabiliser block for polymerisation-induced self-assembly in aqueous media

A series of near-monodisperse poly(N-2-(methacryloyloxy)ethyl pyrrolidone) (PNMEP) homopolymers was prepared via reversible addition-fragmentation chain transfer (RAFT) solution polymerisation of NMEP in ethanol at 70 °C using a carboxylic acid-functional RAFT agent. The mean degree of polymerisation (DP) was varied from 19 to 89 and acid titration indicated end-group pK a values of 5.07-5.44. Turbidimetry studies indicated that homopolymer cloud points were significantly higher at pH 7 (anionic carboxylate) than at pH 3 (neutral carboxylic acid). Moreover, this enhanced hydrophilic character enabled PNMEP to be used as a steric stabiliser for aqueous polymerisation-induced self-assembly (PISA) syntheses. Thus, a PNMEP 42 precursor was chain-extended via RAFT aqueous dispersion polymerisation of 2-hydroxypropyl methacrylate (HPMA) at 44 °C. A series of PNMEP 42 -PHPMA x diblock copolymers were synthesised using this protocol, with target PHPMA DPs of 150 to 400. High conversions were achieved and a linear evolution in M n with increasing PHPMA DP was observed. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) studies confirmed a spherical morphology in all cases. The nanoparticles flocculated either below pH 4.5 (owing to protonation) or on addition of 60 mM KCl (as a result of charge screening). Thus the anionic end-groups on the PNMEP stabiliser chains make an important contribution to the overall colloidal stability. Similarly, a PNMEP 53 macro-CTA was chain-extended via RAFT aqueous emulsion polymerisation of 2-ethoxyethyl methacrylate (EEMA) at 44 °C. Again, a neutral solution pH was critical for the synthesis of colloidally stable nanoparticles. High conversions were achieved as the target PEEMA DP was varied between 100 and 600 and a linear evolution in molecular weight with PEEMA DP was confirmed by chloroform GPC studies. DLS experiments indicated a monotonic increase in nanoparticle diameter with PEEMA DP and TEM studies confirmed a spherical morphology in each case. In summary, PNMEP can be used as a water-soluble steric stabiliser for aqueous PISA syntheses provided that it contains an anionic carboxylate end-group to enhance its hydrophilic character

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: RAFT agent design

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Poly(<I>N</I>-vinylpyrrolidone-<I>b</I>-(gamma-benzyl-L-glutamate)) � Synthesis and self-assembly into pH-sensitive micelles

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Synthesis, characterization, and self-assembly of poly(<I>N</I>-vinylpyrrolidone)-<I>block</I>-poly(vinyl acetate).

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