Library Of Copolymers Research Articles

Effect of Molecular Parameters on the Architecture and Membrane Properties of 3D Assemblies of Amphiphilic Copolymers

Reliable prediction of the 3D structure of self-assembled amphiphilic copolymers is essential for applications in which specificity has to be carefully controlled, as for example in nanomedicine. Since supramolecular assemblies are strongly affected by the chemical nature of block copolymers and the preparation methods, it is essential to understand the influence of such parameters on the self-assembly process. We have now successfully synthesized a library of amphiphilic block copolymers, poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline) (PDMS-b-PMOXA), and investigated the molecular parameters and self-assembly conditions that generate a specific architecture in particular polymersome. We found that 3D assemblies are strongly affected by the preparation method, but not by the initial concentration of block copolymer and solution pH. The phase diagrams of self-assembly behavior show a strong influence of the hydrophilic to hydrophobic ratio (fPMOXA), and the molecular mass of each block. In particular, the formation of polymersomes was possible only for block copolymers with high molecular mass PDMS and low fPMOXA values. A combination of very low molecular mass PDMS and small fPMOXA values induced formation of worm-like micelles, while low molecular mass PDMS and high fPMOXA values generated a mixture of small micelles and spherical particles. The polymersome membranes were characterized by electron paramagnetic resonance, which indicated a multilayer structure (PMOXA outer layer, PDMS middle part, and PMOXA inner layer) with low flexibility and permeability. Addition of detergent increased both the flexibility and permeability of the PDMS block, which was proven to act as a barrier layer for the membranes.

One pot synthesis of higher order quasi-block copolymer librariesviasequential RAFT polymerization in an automated synthesizer

The utility of automated high-throughput methods for the one pot synthesis of functional polymers of increased complexity is reported.

Rapid and Systematic Access to Quasi‐Diblock Copolymer Libraries Covering a Comprehensive Composition Range by Sequential RAFT Polymerization in an Automated Synthesizer

A versatile, cost-effective approach to the rapid, fully unattended preparation of systematic quasi-diblock copolymer libraries via sequential RAFT polymerization in an automated synthesizer is reported. The procedure is demonstrated with the synthesis of a 23 member library of low dispersity poly(butyl methacrylate)-quasiblock-poly(methyl methacrylate) covering a wide (fivefold) range of molar mass for the second block in a one-pot, sequential, RAFT polymerization.

Dual pH- and temperature-responsive microparticles for protein delivery to ischemic tissues

Injectable “smart” microspheres that are sensitive to both temperature and pH have been fabricated and tested for controlled delivery of therapeutic proteins to ischemic skeletal muscle. A library of copolymers composed of N-isopropyl acrylamide (NIPAAm), propyl acrylic acid (PAA), and butyl acrylate (BA) was used to fabricate microspheres using a double emulsion method, and an optimal formulation made from copolymers composed of 57mol.% NIPAAm, 18mol.% PAA and 25mol.% BA copolymers was identified. At 37°C and pH representative of ischemic muscle (i.e. pH 5.2–7.2), these microspheres produced sustained, diffusion-controlled release, and at normal, physiological pH (i.e. pH 7.4), they underwent dissolution and rapid clearance. Delivery of fibroblast growth factor 2 was used to confirm that protein bioactivity was retained following microsphere encapsulation/release based on a dose-dependent increase in NIH3T3 fibroblast proliferation in vitro. Microsphere-loaded or free Cy5.5-labeled albumin was injected into ischemic and control gastrocnemii of mice following unilateral induction of hind limb ischemia to model peripheral arterial disease. In the ischemic limb at days 3.5 and 7, there was higher local retention of the protein delivered via microspheres relative to injected free protein (p<0.05). However, clearance of protein delivered via microspheres was equivalent to free protein at later time points that correspond to ischemic recovery in this model. Finally, histological analysis of the gastrocnemius revealed that the polymeric microspheres did not produce any microscopic signs of toxicity near the injection site. These combined results suggest that the pH- and temperature-responsive microspheres presented herein are a promising technological platform for controlled protein delivery to ischemic tissue.

Quasi-block copolymer libraries on demand via sequential RAFT polymerization in an automated parallel synthesizer

A convenient synthetic method for the systematic preparation of quasi-diblock copolymer libraries utilizing a sequential RAFT polymerization strategy is described. This method utilizes a parallel synthesizer and allows the unattended and fully automated synthesis of this type of library in a short period of time. The materials obtained in this investigation have shown properties very similar to those expected in “pure” diblock copolymers as determined by differential scanning calorimetry. The described method can be a useful and less expensive alternative for the rapid preparation and screening of block copolymer libraries.

The balance between intramolecular hydrogen bonding, polymer solubility and rigidity in single-chain polymeric nanoparticles

A library of copolymers with pendant, protected ureido-pyrimidinone (UPy) groups was prepared applying controlled polymerization techniques. The polymer backbones were based on polyacrylate, polymethacrylate, polystyrene and polynorbornene and differ in stiffness, molecular weight and the linking moiety between the backbone and the UPy group. In all cases, the percentage of protected UPy groups was kept constant. The effect of solvent on the behaviour of the polymers before and after removal of the protecting groups was evaluated in, among others, chloroform and tetrahydrofuran (THF). After deprotection of the UPy protecting group, the UPys dimerize via four-fold H-bonding in THF, inducing a collapse into single-chain polymeric nanoparticles (SCPNs), as evidenced by a combination of 1H-NMR spectroscopy, size-exclusion chromatography and dynamic light scattering. In chloroform, on the other hand, dimerization of the UPy groups is present but interchain interactions occur as well, resulting in less-defined SCPNs. Remarkably, the flexibility of the polymer backbone, the polymer molecular weight and the nature of the linker unit all do not affect SCPN formation. In contrast, the interaction between solvent and the UPy moiety is a critical parameter for SCPN formation. For example, strong intramolecular dimerization of the UPys is observed in THF while interparticle interactions are suppressed. From this investigation we conclude that a wide variety of polymer backbones are suitable for polymer collapse via supramolecular interactions and thus allow for the formation of SCPNs but that the solvent choice is crucial to enhance intramolecular H-bonding and, at the same time, to suppress interparticle interactions.

Poly(methyl methacrylate-block-vinyl-m-triphenylamine): synthesis by RAFT polymerization and melt-state self-assembly

Block copolymers (BCP)s containing electro-active hole-transport components such as triphenylamine-based polymers are attractive for organic electronic applications in which well-defined nanoscale structures are desirable. In this work, we synthesized poly(methyl methacrylate-block-vinyl-m-triphenylamine) (PMMA-b-PVmTPA) BCPs via reversible addition-fragmentation chain transfer (RAFT) polymerization and subsequently explored their melt-state self-assembly in the PMMA-rich phase regime. A library of diblock copolymers was generated by chain-extending several different poly(methyl methacrylate) (PMMA) macroinitiators with vinyl-m-triphenylamine monomer (VmTPA). These PMMA-b-PVmTPA diblock copolymers self-assembled into a variety of well-defined nanostructures over the studied compositional range (PVmTPA volume fractions [fPVmTPA] from 0.25 to 0.33), forming hexagonally packed cylinders (HEX) at fPVmTPA of 0.27 and below, network-like hexagonally perforated lamellae (HPL) at an intermediate fPVmTPA = 0.29, and lamellae (LAM) at fPVmTPA of 0.30 and above, as determined by small-angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) analyses. Additionally, we found a thermally reversible order-order transition (OOT) from HPL to HEX upon heating, indicating that the HPL morphology likely was stable at lower temperatures for this system. Finally, we present an experimental phase diagram based on the assigned nanostructures as a function of PMMA-b-PVmTPA molecular weight and fPVmTPA. These results provide valuable guidance for targeting desirable morphologies in functional nanomaterials that incorporate the TPA functional group.

Synthesis and cellular compatibility of multi-block biodegradable poly(ε-caprolactone)-based polyurethanes.

A library of block copolymers was synthesized by varying the molecular weight of the poly(ε-caprolactone) (PCL)-diol soft segment (Mw = 850, 3050, 3700 or 7000), which was reacted with methylene diphenyl diisocyanate (MDI), 1,4-phenylene diisocyanate (PDI), 1,1'-methylenebis(4-isocyanatocyclohexane) (HMDI), or 2,4-toluene diisocyanate (TDI) with 1,4-butanediol (BD) or ethylene glycol (EG) added as chain extenders. Thermal and X-ray measurements indicated that the crystalline structure of the copolymers was largely dependent on the chain length of the PCL-diol, with no crystallization taking place with the smallest diol (Mw = 850) using MDI, TDI or HMDI. However, the copolymers produced from a PCL-diol (Mw = 850) and PDI and chain extenders (BD or EG) showed resolved crystalline peaks while no peaks appeared with other diisocyanates. Hydrolytic degradation studies demonstrated a faster degradation rate in the case of more amorphous copolymers than semi-crystalline copolymers. The cellular compatibility of the copolymers was evaluated by fabricating the entire library of polymers in a microarray format and in vitro cell culture, demonstrating that all the 57 copolymers supported cellular attachment and growth.

Triarylamine polymers of bridged phenylenes by (N-heterocyclic carbene)-palladium catalysed C–N coupling

A library of triarylamine copolymers with 2,7-fluorene, 3,7-dibenzo[b,d]thiophene and 2,7-carbazole units incorporated in the polymer backbone is reported. The polymers were synthesised by using C–N coupling of anilines and dibromoarenes, catalysed by N-heterocyclic carbene complexes of palladium. The properties of the polymers were tuned by changing the nature of the fused ring structure and the substitution of the pendant benzene of the arylamine. The use of these polymers as the charge transporting layer of an OFET is demonstrated with the highest mobility found for polymers derived from 2,7-dibromo-9,9′-dioctylfluorene and 4-methoxy-2-methylaniline.

Dual pH and temperature responsive helical copolymer libraries with pendant chiral leucine moieties

Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to afford two different chiral copolymer series having opposite chiroptical properties based on 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and Boc-L/D-leucine methacryloyloxyethyl ester (Boc-L/D-Leu-HEMA) with varying co-monomer proportions. The random nature of the copolymers was indicated by the reactivity ratios of the two monomers for the two systems (MEO2MA with Boc-L-Leu-HEMA and Boc-D-Leu-HEMA), and further supported by smooth variation of the single glass transition temperature (Tg) determined from differential scanning calorimetry (DSC). With an increasing amino acid content in the copolymer, the specific rotation and molar ellipticity values increased, as examined by polarimeter and circular dichroism (CD) spectroscopy, respectively. After Boc-group cleavage under acidic conditions, all the copolymers exhibited cationic nature, as confirmed by dynamic light scattering (DLS), as well as the dual thermo and pH-dependent solubility behaviour in aqueous solution. The temperature induced phase transition of these copolymers was investigated as a function of the copolymer compositions over the pH range from 5.5 to 6.5 using a UV-Vis spectrophotometer. Furthermore, the chiral recognition ability of the synthesized monomers and homopolymers towards 1,1′-bi-2-naphthol (rac-BINOL) was studied by 1H NMR spectroscopy.

Formation of dynamic metallo-copolymers by inkjet printing: towards white-emitting materials

The variation of the central chromophore in bisterpyridine ZnII coordination polymers allowed the assembly of blue-, green- and red-emitting materials. The dynamic nature of the ZnII complex enabled the systematic assembly of a library of statistical copolymers in an efficient way by simply mixing the respective homopolymer solutions. Depending on the ratios used and the consequent energy transfer processes, the resulting emission colors can be tailored. The kinetic lability of the ZnII bisterpyridine polymers was, moreover, utilized to assemble thin films of statistical copolymers in a simple and material-saving manner by inkjet printing. For this purpose, the pure color inks were printed separately on top of each other, followed by one solvent layer to enable the assembly of statistical copolymers. The emission spectra of the resulting films are bathochromically shifted, due to aggregation of the chromophores. The obtained data allowed an estimation of CIE coordinates of the emission color for most ratios of the three polymers used and, thereby, to produce tailor-made emission colors.

Polyethylene glycol–grafted polyethylenimine used to enhance adenovirus gene delivery

An improved adenoviral-based gene delivery vector was developed by complexing adenovirus (Ad) with a biocompatible, grafted copolymer PEG-g-PEI composed of polyethylene glycol (PEG) and polyethylenimine (PEI). Although an Ad-based gene vector is considered relatively safe, its native tropism, tendency to elicit an immune response, and susceptibility to inactivating antibodies makes the virus less than ideal. The goal of the current study was to determine whether Ad could be complexed with a PEG-g-PEI copolymer that would enable the virus to transduce cells lacking the Ad receptor, while avoiding the issues commonly associated with PEI. A copolymer library was synthesized using 2 kDa PEG and either linear or branched PEI (25 kDa) with a PEG to PEI grafting ratio of 10, 20, or 30. The results of the study indicate that PEG-g-PEI/Ad complexes are indeed able to transduce CAR-negative NIH 3T3 cells. The results also demonstrate that the PEG-g-PEI/Ad complexes are less toxic, less hemolytic, and more appropriately sized than PEI/Ad complexes.

Enhancement of Poly(vinyl ester) Solubility in Supercritical CO2 by Partial Fluorination: The Key Role of Polymer–Polymer Interactions

An enhancement of poly(vinyl ester) solubility in supercritical carbon dioxide (sc-CO(2)) can be achieved by decreasing the strength of the polymer-polymer interactions. To demonstrate this, a library of statistical copolymers of vinyl acetate and vinyl trifluoroacetate was synthesized by RAFT/MADIX polymerization with varying compositions at a given number-average molecular weight. These copolymers exhibited unprecedentedly low cloud-point pressures in sc-CO(2) at 40 °C compared with previously reported poly(vinyl esters). Surface tension measurements combined with a computational approach evidenced the prominent role played by polymer-polymer interactions.

Tuning h‐bond capability of hydroxylated‐poly(2,3,4,5,6‐pentafluorostyrene) grafted copolymers prepared by chemoselective and versatile thiol‐para‐fluoro “click‐type” coupling with mercaptoalcohols

AbstractNovel H‐bond donor copolymers were designed by a versatile “click type” grafting reaction of unprotected mercaptoalcohols onto poly(2,3,4,5,6‐pentafluorostyrene) (PPFS). As demonstrated by 19F NMR and Fourier transform infrared spectroscopy (FTIR) analyses, the reaction appears to be chemoselective as the SH groups solely react onto the para‐fluoro position of the PFS units. The nucleophilic substitution was successfully performed with two mercaptoalcohols bearing either one or two hydroxyl groups. By carefully selecting the experimental conditions, a library of copolymers with various degree of substitution up to 95% was obtained in a reasonable timescale through kinetic control. By turbidity analysis, the ability of these functional polymers to form in solution interpolymer complexes with poly(4‐vinyl pyridine) was shown to be tunable by adjusting the molecular characteristics. FTIR, X‐ray photoelectron spectroscopy, and Differential scanning calorimetry evidence that different types of blends (immiscible, partially or totally miscible, and complex) can be achieved, and that the driving force of the interaction originates from H‐bond. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Cationic Spacer Arm Design Strategy for Control of Antimicrobial Activity and Conformation of Amphiphilic Methacrylate Random Copolymers

Antimicrobial and hemolytic activities of amphiphilic random copolymers were modulated by the structure of the cationic side chain spacer arms, including 2-aminoethylene, 4-aminobutylene, and 6-aminohexylene groups. Cationic amphiphilic random copolymers with ethyl methacrylate (EMA) comonomer were prepared with a range of comonomer fractions, and the library of copolymers was screened for antimicrobial and hemolytic activities. Copolymers with 4-aminobutylene cationic side chains showed an order of magnitude enhancement in their antimicrobial activity relative to those with 2-aminoethylene spacer arms, without causing adverse hemolysis. When the spacer arms were further elongated to hexylene, the copolymers displayed potent antimicrobial and hemolytic activities. The 4-aminobutylene side chain appears to be the optimal spacer arm length for maximal antimicrobial potency and minimal hemolysis, when combined with hydrophobic ethylmethacrylate in a roughly 70/30 ratio. The copolymers displayed relatively rapid bactericidal kinetics and broad-spectrum activity against a panel of Gram-positive and Gram-negative bacteria. The effect of the spacer arms on the polymer conformation in the membrane-bound state was investigated by molecular dynamics simulations. The polymer backbones adopt an extended chain conformation, parallel to the membrane surface. A facially amphiphilic conformation at the membrane surface was observed, with the primary ammonium groups localized at the lipid phoshophate region and the nonpolar side chains of EMA comonomers buried in the hydrophobic membrane environment. This study demonstrates that the antimicrobial activity and molecular conformation of amphiphilic methacrylate random copolymers can be modulated by adjustment of cationic side chain spacer arms.

Squaric Acid Mediated Synthesis and Biological Activity of a Library of Linear and Hyperbranched Poly(Glycerol)–Protein Conjugates

Polymer-protein conjugates generated from side chain functional synthetic polymers are attractive because they can be easily further modified with, for example, labeling groups or targeting ligands. The residue specific modification of proteins with side chain functional synthetic polymers using the traditional coupling strategies may be compromised due to the nonorthogonality of the side-chain and chain-end functional groups of the synthetic polymer, which may lead to side reactions. This study explores the feasibility of the squaric acid diethyl ester mediated coupling as an amine selective, hydroxyl tolerant, and hydrolysis insensitive route for the preparation of side-chain functional, hydroxyl-containing, polymer-protein conjugates. The hydroxyl side chain functional polymers selected for this study are a library of amine end-functional, linear, midfunctional, hyperbranched, and linear-block-hyperbranched polyglycerol (PG) copolymers. These synthetic polymers have been used to prepare a diverse library of BSA and lysozyme polymer conjugates. In addition to exploring the scope and limitations of the squaric acid diethylester-mediated coupling strategy, the use of the library of polyglycerol copolymers also allows to systematically study the influence of molecular weight and architecture of the synthetic polymer on the biological activity of the protein. Comparison of the activity of PG-lysozyme conjugates generated from relatively low molecular weight PG copolymers did not reveal any obvious structure-activity relationships. Evaluation of the activity of conjugates composed of PG copolymers with molecular weights of 10000 or 20000 g/mol, however, indicated significantly higher activities of conjugates prepared from midfunctional synthetic polymers as compared to linear polymers of similar molecular weight.

Protective Effects of Nonionic Triblock Copolymers on Bile Acid-Mediated Epithelial Barrier Disruption

Translocation of bacteria and other luminal factors from the intestine following surgical injury can be a major driver of critical illness. Bile acids have been shown to play a key role in the loss of intestinal epithelial barrier function during states of host stress. Experiments to study the ability of nonionic block copolymers to abrogate barrier failure in response to bile acid exposure are described. In vitro experiments were performed with the bile salt sodium deoxycholate on Caco-2 enterocyte monolayers using transepithelial electrical resistance to assay barrier function. A bisphenol A coupled triblock polyethylene glycol (PEG), PEG 15-20, was shown to prevent sodium deoxycholate-induced barrier failure. Enzyme-linked immunosorbent assay, lactate dehydrogenase, and caspase 3-based cell death detection assays demonstrated that bile acid-induced apoptosis and necrosis were prevented with PEG 15-20. Immunofluorescence microscopic visualization of the tight junctional protein zonula occludens 1 (ZO-1) demonstrated that PEG 15-20 prevented significant changes in tight junction organization induced by bile acid exposure. Preliminary transepithelial electrical resistance-based studies examining structure-function correlates of polymer protection against bile acid damage were performed with a small library of PEG-based copolymers. Polymer properties associated with optimal protection against bile acid-induced barrier disruption were PEG-based compounds with a molecular weight greater than 10 kd and amphiphilicity. The data demonstrate that PEG-based copolymer architecture is an important determinant that confers protection against bile acid injury of intestinal epithelia.

Block Copolymer Micelles for Controlled Delivery of Glycolytic Enzyme Inhibitors

To develop block copolymer micelles as an aqueous dosage form for a potent glycolytic enzyme inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). The micelles were prepared from poly(ethylene glycol)-poly(aspartate hydrazide) [PEG-p(HYD)] block copolymers to which 3PO was conjugated through an acid-labile hydrazone bond. The optimal micelle formulation was determined following the screening of block copolymer library modified with various aromatic and aliphatic pendant groups. Both physical drug entrapment and chemical drug conjugation methods were tested to maximize 3PO loading in the micelles during the screening. Particulate characterization showed that the PEG-p(HYD) block copolymers conjugated with 3PO (2.08∼2.21wt.%) appeared the optimal polymer micelles. Block copolymer compositions greatly affected the micelle size, which was 38nm and 259nm when 5kDa and 12kDa PEG chains were used, respectively. 3PO release from the micelles was accelerated at pH 5.0, potentiating effective drug release in acidic tumor environments. The micelles retained biological activity of 3PO, inhibiting various cancer cells (Jurkat, He-La and LLC) in concentration ranges similar to free 3PO. A novel micelle formulation for controlled delivery of 3PO was successfully prepared.

Synthesis and Assembly of Butyl Rubber–Poly(ethylene oxide) Graft Copolymers: From Surface Patterning to Resistance to Protein Adsorption

The patterning of copolymers on surfaces is of interest both for a fundamental understanding of polymer assembly processes and for applications ranging from microelectronics to biomaterials. Graft copolymers can provide new opportunities to control polymer composition and architecture, thus opening possibilities for new assembly processes and patterns. In this work, the reaction of a butyl rubber derivative functionalized with activated carbonates along the polymer backbone was reacted with amine terminated poly(ethylene oxide) (PEO–NH2) to provide butyl rubber–PEO graft copolymers. The high efficiency of this reaction allowed for control of the PEO content by the number of equivalents of PEO–NH2 used and its molecular weight, providing a small library of graft copolymers. This approach also provided butyl rubber–PEO graft copolymers with unprecedentedly high PEO content. Thin films of the polymers, prepared by spin-casting were studied by a number of techniques including atomic force microscopy, polarize...

Synthesis of microcapsules via reactive surfactants

A statistical library of well-defined ionic and non-ionic amphiphilic block copolymers of P(MMA/HEMA)-b-PDMAEMA and PEG-b-P(MMA/HEMA) were synthesised via living radical polymerisation employing the macroinitiator technique. All the block copolymers show monomodal peaks and narrow weight distributions, indicating they were obtained in controlled manner. Those copolymers were further modified in order to prepare inisurfs and surfmers. This yielded a selection of active surfactants of desired molecular weight and low polydispersity. Soap-free miniemulsion polymerisations of butyl methacrylate were carried out using the obtained active surfactants to prepare core–shell microcapsules in which various concentrations of inert oil, hexadecane, as a model system were encapsulated. The influence of the block copolymer structure on the particle formation was studied. The core–shell nature of the particles could be confirmed using scanning electron microscopy. Up to 66% of hexadecane could be incorporated in PBMA microcapsules.