Anionic multiblock core cross-linked star copolymers via RAFT polymerization

Poly(2-acrylamido-2-methylpropane sulfonic acid) is a polyelectrolyte currently used in numerous industrial applications. Herein, we report the use of reversible addition fragmentation chain transfer (RAFT) polymerization to prepare a range of well-defined homopolymers and block copolymers of 2-acrylamido-2-methylpropane sulfonic acid (AMPS®) and either N-hydroxyethyl acrylamide (HEAm) or 4-acryloylmorpholine (NAM) as a comonomer. We also describe the one-pot synthesis of multiblock core cross-linked star copolymers of AMPS® and HEAm with low dispersities (<1.3). The influence of several parameters such as the cross-linker type, cross-linker to chain transfer agent (CTA) ratio, arm length and composition on the polymerization efficiency are investigated

Investigating cell uptake of guanidinium-rich RAFT polymers : impact of comonomer and monomer distribution

A range of well-defined guanidinium-rich linear polymers with demonstrable efficiency for cellular internalization were developed. A protected guanidinium-functional acrylamide monomer (di-Boc-guanidinium ethyl acrylamide, GEAdiBoc) was synthesized and then polymerized via RAFT polymerization to yield well-defined homopolymers, which were then deprotected and functionalized with a fluorescein dye to observe and quantify their cellular uptake. The cellular uptake of these homopolymers was first compared to analogous polyarginines, which are commonly used in modern drug delivery. Following this, a range of well-defined guanidinium-rich copolymers were prepared in which the monomer distribution was varied using a convenient one-pot sequential RAFT polymerization approach. Systematic quantification of the cell uptake of these compounds, supported by fluorescent confocal microscopy data, revealed that while the overall hydrophobicity of the resulting copolymers has a direct impact on the amount of copolymer taken up by cells, the distribution of monomers has an influence on both the extent of uptake and the relative extent to which each route of internalization (endocytosis vs direct translocation) is exploited

Extracting and Unfolding a Stratigraphic Unit to Update Property Population

International audienceWith the wide usage of geo-modelling tools, users could have the need to enhance their previous geostatiscal population without rebuilding an entire stratigraphic model In this paper we explain how we can extract non explicit information from a stratigraphic model (reference iso-chronological surfaces, faults used to constraint the model), and then, use this information to realise 3D flattening on iso-chronological surfaces prior to geostatiscal population. Three methods were presented here: traditional by topological correspondence, vertical shear and an original isometric unfolding process based on the minimization of the elastic tensor deformation. These methods could be applied for every type of deposit: Horizontal, Parallel to Top, parallel to Bottom, Proportional. Then, we compare the application of these methods on several case studies and develop the advantages to reengineer a stratigraphic model and repopulate it after flattening. Even if the "traditional" and vertical shear methods could be applied on certain situations, following multiple test bed as the ones presented in this paper, we are thinking that the isometric unfolding presented here is much reliable. As a consequence, we will exploit more and more this isometric unfolding method in the next future and process each lithostratigraphic unit independently than the others

Sulfonated copolymers as heparin-mimicking stabilizer of fibroblast growth factor : size, architecture, and monomer distribution effects

Fibroblast growth factors (FGF) are involved in a wide range of biological processes such as cell proliferation and differentiation. In living organisms, the binding of FGF to its receptors are mediated through electrostatic interactions between FGF and naturally occurring heparin. Despite its prevalent use in medicine, heparin carries notable limitations, namely; its extraction from natural sources (expensive, low yield and extensive purification), viral contamination, and batch-to-batch heterogeneity. In this work a range of synthetic homopolymers and copolymers of sodium 2-acrylamido-2-methylpropane sulfonate (AMPS®) were evaluated as potential FGF stabilisers. This was studied by measuring the proliferation of BaF3-FR1c cells, as a model assay, and the results will be compared with the natural stabilisation and activation of FGF by heparin. This study explores the structure-activity relationship of these polysulfonated polymers with a focus on the effect of molecular weight, co-monomer type, charge dispersion and polymer architecture on protein stabilisation

Influence of block versus random monomer distribution on the cellular uptake of hydrophilic copolymers

The use of polymers has revolutionized the field of drug delivery in the past two decades. Properties such as polymer size, charge, hydrophilicity, or branching have all been shown to play an important role in the cellular internalization of polymeric systems. In contrast, the fundamental impact of monomer distribution on the resulting biological properties of copolymers remains poorly studied and is always only investigated for biologically active self-assembling polymeric systems. Here, we explore the fundamental influence of monomer distribution on the cellular uptake of nonaggregating and biologically passive copolymers. Reversible addition–fragmentation chain-transfer (RAFT) polymerization was used to prepare precisely defined copolymers of three hydrophilic acrylamide monomers. The cellular internalization of block copolymers was compared with the uptake of a random copolymer where monomers are statistically distributed along the chain. The results demonstrate that monomer distribution in itself has a negligible impact on copolymer uptake

Targeting intracellular, multi-drug resistant Staphylococcus aureus with guanidinium polymers by elucidating the structure-activity relationship

Intracellular persistence of bacteria represents a clinical challenge as bacteria can thrive in an environment protected from antibiotics and immune responses. Novel targeting strategies are critical in tackling antibiotic resistant infections. Synthetic antimicrobial peptides (SAMPs) are interesting candidates as they exhibit a very high antimicrobial activity. We first compared the activity of a library of ammonium and guanidinium polymers with different sequences (statistical, tetrablock and diblock) synthesized by RAFT polymerization against methicillin-resistant S. aureus (MRSA) and methicillin-sensitive strains (MSSA). As the guanidinium SAMPs were the most potent, they were used to treat intracellular S. aureus in keratinocytes. The diblock structure was the most active, reducing the amount of intracellular MSSA and MRSA by two-fold. We present here a potential treatment for intracellular, multi-drug resistant bacteria, using a simple and scalable strategy

Probing the dynamic nature of self-assembling cyclic peptide-polymer nanotubes in solution and in mammalian cells

Self-assembling cyclic peptide–polymer nanotubes have emerged as a fascinating supramolecular system, well suited for a diverse range of biomedical applications. Due to their well-defined diameter, tunable peptide anatomy, and ability to disassemble in situ, they have been investigated as promising materials for numerous applications including biosensors, antimicrobials, and drug delivery. Despite this continuous effort, the underlying mechanisms of assembly and disassembly are still not fully understood. In particular, the exchange of units between individual assembled nanotubes has been overlooked so far, despite its knowledge being essential for understanding their behavior in different environments. To investigate the dynamic nature of these systems, cyclic peptide–polymer nanotubes are synthesized, conjugated with complementary dyes, which undergo a Förster resonance energy transfer (FRET) in close proximity. Model conjugates enable to demonstrate not only that their self-assembly is highly dynamic and not kinetically trapped, but also that the self-assembly of the conjugates is strongly influenced by both solvent and concentration. Additionally, the versatility of the FRET system allows studying the dynamic exchange of these systems in mammalian cells in vitro using confocal microscopy, demonstrating the exchange of subunits between assembled nanotubes in the highly complex environment of a cell

Tuning the structure, stability and responsivity of polymeric arsenical nanoparticles using polythiol cross-linkers

The use of organic arsenicals in polymer chemistry and biomaterials science is limited despite the distinctive and versatile chemistry of arsenic. The interchangeable oxidation states of arsenic and the subsequent changes in chemical properties make it a promising candidate for redox-responsive materials. Thus, reversible addition–fragmentation chain transfer (RAFT) polymerization has been employed for the first time to synthesize thermoresponsive organic arsenical containing block copolymers. The polymers undergo simultaneous self-assembly and cross-linking, via the organic arsenical pendant groups, under reductive conditions (to reduce As(V) to As(III)) in the presence of polythiol reagents as cross-linkers. The formation of As–S bonds stabilizes the nanoparticles formed (Dh = 19–29 nm) and enables the stability and responsivity to oxidative stress of the particles, in aqueous and model biological solutions, to be tuned as a function of the number of thiols in the cross-linker or the [SH]/[As] stoichiometric ratio. The parent block copolymers and nanoparticles are nontoxic in vitro, and the tunable responsivity of these nanoparticles and the (bio)chemical activity of organic arsenical reagents could be advantageous for targeted drug delivery and the other bio(nano)medical applications. To the best our knowledge, this is the first time that arsenic–thiolate (As–S) bonding has been employed for stimuli-responsive cross-linking of polymeric nanoparticles

Flow at an Ogee Crest Axis for a Wide Range of Head Ratios: Theoretical Model

peer reviewedThe discharge coefficient of an ogee crest is a function of the ratio of the effective head to the design head. The purpose of the present study is to derive a theoretical model of this relation, which does not depend on empirical coefficients and whose predictions over a wide range of head ratios are accurate enough for practical use. The developments consider unsubmerged ogee crests without approach flow or lateral contraction effects, heads large enough to enable surface tensions to be neglected, and heads small enough to avoid flow separation. The method is based on potential flow theory, depth integration in a curvilinear reference frame, and critical flow theory. The characteristics of the crest shape are defined by the trajectory of a free jet passing over the crest at the design head. The dimensionless equations show that the position of the critical section is not at the apex of the crest. Nevertheless, they also suggest an approximate equation at the apex of the crest from which the discharge coefficient is derived, together with the local water depth, velocity, and pressure distribution. The results compare well with experimental data for head ratios between 0 and 5, which validates the underlying assumptions of the theoretical model.11. Sustainable cities and communitie

Cyclic peptide-poly(HPMA) nanotubes as drug delivery vectors : in vitro assessment, pharmacokinetics and biodistribution

Size and shape have progressively appeared as some of the key factors influencing the properties of nanosized drug delivery systems. In particular, elongated materials are thought to interact differently with cells and therefore may allow alterations of in vivo fate without changes in chemical composition. A challenge, however, remains the creation of stable self-assembled materials with anisotropic shape for delivery applications that still feature the ability to disassemble, avoiding organ accumulation and facilitating clearance from the system. In this context, we report on cyclic peptide-polymer conjugates that self-assemble into supramolecular nanotubes, as confirmed by SANS and SLS. Their behaviour ex and in vivo was studied: the nanostructures are non-toxic up to a concentration of 0.5 g L and cell uptake studies revealed that the pathway of entry was energy-dependent. Pharmacokinetic studies following intravenous injection of the peptide-polymer conjugates and a control polymer to rats showed that the larger size of the nanotubes formed by the conjugates reduced renal clearance and elongated systemic circulation. Importantly, the ability to slowly disassemble into small units allowed effective clearance of the conjugates and reduced organ accumulation, making these materials interesting candidates in the search for effective drug carriers