Straightforward preparation of a tough and stretchable ion gel.

Ion gels, polymer networks swollen by ionic liquids, are expected to be applied to wearable devices that are tolerant to repeated stretching. High strength and excellent stretchability was achieved due to the numerous physical cross-links with abundant polymer chain entanglements in addition to a small number of immobile chemical cross-links, even though the ion gel was prepared by a facile methodology.

Effect of Gold Nanoparticle Size on Regulated Catalytic Activity of Temperature-Responsive Polymer-Gold Nanoparticle Hybrid Microgels.

Gold nanoparticles (AuNPs) possess attractive electronic, optical, and catalytic properties, enabling many potential applications. Poly(N-isopropyl acrylamide) (PNIPAAm) is a temperature-responsive polymer that changes its hydrophilicity upon a slight temperature change, and combining PNIPAAm with AuNPs allows us to modulate the properties of AuNPs by temperature. In a previous study, we proposed a simpler method for designing PNIPAAm-AuNP hybrid microgels, which used an AuNP monomer with polymerizable groups. The size of AuNPs is the most important factor influencing their catalytic performance, and numerous studies have emphasized the importance of controlling the size of AuNPs by adjusting their stabilizer concentration. This paper focuses on the effect of AuNP size on the catalytic activity of PNIPAAm-AuNP hybrid microgels prepared via the copolymerization of N-isopropyl acrylamide and AuNP monomers with different AuNP sizes. To quantitatively evaluate the catalytic activity of the hybrid microgels, we monitored the reduction of 4-nitrophenol to 4-aminophenol using the hybrid microgels with various AuNP sizes. While the hybrid microgels with an AuNP size of 13.0 nm exhibited the highest reaction rate and the apparent reaction rate constant (kapp) of 24.2 × 10-3 s-1, those of 35.9 nm exhibited a small kapp of 1.3 × 10-3 s-1. Thus, the catalytic activity of the PNIPAAm-AuNP hybrid microgel was strongly influenced by the AuNP size. The hybrid microgels with various AuNP sizes enabled the reversibly temperature-responsive on-off regulation of the reduction reaction.

UCST-Type Thermoresponsive Sol-Gel Transition Triblock Copolymer Containing Zwitterionic Polymer Blocks.

Thermoresponsive sol-gel transition polymers are of significant interest because of their fascinating biomedical applications, including as drug reservoirs for drug delivery systems and scaffolds for tissue engineering. Although extensive research has been conducted on lower critical solution temperature (LCST)-type sol-gel transition polymers, there have been few reports on upper critical solution temperature (UCST)-type sol-gel transition polymers. In this study, we designed an ABA-type triblock copolymer composed of a poly(ethylene glycol) (PEG) block and zwitterionic polymer blocks that exhibit UCST-type thermoresponsive phase transitions. A sulfobetaine (SB) monomer with both ammonium and sulfonate (-SO3) groups in its side chain or a sulfabetaine (SaB) monomer with both ammonium and sulfate (-OSO3) groups in its side chain was polymerized from both ends of the PEG block via reversible addition-fragmentation chain-transfer (RAFT) polymerization to obtain PSB-PEG-PSB and PSaB-PEG-PSaB triblock copolymers, respectively. Although an aqueous solution containing the PSB-PEG-PSB triblock copolymer showed an increase in viscosity upon cooling, it did not undergo a sol-to-gel transition. In contrast, a sol-to-gel transition was observed when a phosphate-buffered saline containing PSaB-PEG-PSaB was cooled from 80 °C to 25 °C. The PSaB blocks with -OSO3 groups exhibited a stronger dipole-dipole interaction than conventional SB with -SO3 groups, leading to intermolecular association and the formation of a gel network composed of PSaB assemblies bridged with PEG. The fascinating UCST-type thermoresponsive sol-gel transition properties of the PSaB-PEG-PSaB triblock copolymer suggest that it can provide a useful platform for designing smart biomaterials, such as drug delivery reservoirs and cell culture scaffolds.

Relatively homogeneous network structures of temperature-responsive gels synthesized via atom transfer radical polymerization.

The network structures of poly(N-isopropylacrylamide) (PNIPAAm) gels prepared by atom transfer radical polymerization (ATRP) were compared with those prepared by free radical polymerization (FRP), as a conventional radical polymerization. Temperature-responsive shrinkage was observed in the PNIPAAm gels prepared by ATRP and FRP (ATRP and FRP gels), which depended on the cross-linker content. From the light-scattered intensities, 〈I〉T, measured at the different sample positions, we used the partial heterodyne method to determine the dynamic fluctuation, 〈I〉F, spatial component, 〈I〉C, and correlation length, ξ, of the ATRP and FRP gels, as a function of the cross-linker content and temperature. While there is little difference in 〈I〉F and ξ between the ATRP and FRP gels, 〈I〉C of the ATRP gel was smaller than that of the FRP gel. In addition, we calculated the standard deviation of 〈I〉T for the ATRP and FRP gels, as a function of temperature to quantify the inhomogeneity of the gel networks. The standard deviation revealed that increasing cross-linker content and temperature makes the gel networks more inhomogeneous. The dynamic light scattering (DLS) measurement used to characterize the gel network revealed that ATRP suppresses inhomogeneity more effectively than FRP. The standard deviation of the scattered intensity is used in this study to quantify the inhomogeneity of the network structures. Quantitative evaluations of the inhomogeneity of the network structures by the standard deviation of the scattered intensity are useful in the investigation of the structure-property relationships of gels.

Amphiphilic Liquid Crystalline Polymer Micelles That Exhibit a Phase Transition at Body Temperature.

Liquid crystalline polymers (LCPs), which exhibit unique structures and properties intermediate between those of liquids and solids, are widely utilized as functional and advanced materials for fabricating optical devices and high-performance fibers. This utility stems from their ability to abruptly change their organized structures and mobilities at their liquid crystalline-isotropic phase transition temperatures, similar to the properties of biological membranes. Despite these numerous potential applications of LCPs, no study on their use in medical applications such as drug delivery has been reported. In the present study, we synthesized amphiphilic side-chain LCPs (LCP-g-OEGs, where OEG is oligo(ethylene glycol)) for medical applications, where the LCP-g-OEGs undergo a nematic-isotropic phase transition at body temperature. The LCP-g-OEGs formed micelles with a diameter of approximately 130 nm in aqueous media. The micelles were stable and did not dissociate in aqueous media even when the temperature exceeded the nematic-isotropic phase transition temperature (TNI). Although the release of a dye as a model drug from micelles was suppressed at temperatures lower than TNI, their dye release was drastically enhanced at temperatures higher than TNI. The LCP-g-OEG micelles regulated dye release reversibly in accordance with stepwise changes in temperature, without undergoing dissociation, differing from the behavior of standard temperature-responsive micelles. The temperature-responsive dye release behavior is induced by dramatic changes in their well-organized and dynamic structures as a result of the nematic-isotropic phase transition. These results demonstrate that the LCP-g-OEG micelles have a lot of medical applications as reversibly stimuli-responsive drug carriers.

Design of molecularly imprinted hydrogels with thermoresponsive drug binding sites.

Drug delivery systems (DDS) regulate the spatiotemporal distribution of drugs in vivo to maximize efficacy and minimize side effects. Stimuli-responsive hydrogels, which exhibit a drastic change in volume in response to external stimuli such as temperature and pH, have attracted considerable interest as drug reservoirs for self-regulating DDS, as stimuli-responsive changes in the network size can regulate drug diffusion. However, such hydrogels have the disadvantage of leaking drugs even in the absence of stimulation. Proteins such as hemoglobin have dynamic molecular binding sites that modify their binding capacities by their conformational changes induced when an effector molecule binds to allosteric sites. Such dynamic binding sites are useful for loading drugs into reservoirs because their conformational changes can be used to control drug loading and release. In this study, we prepared thermoresponsive hydrogels with a controlled drug binding capacity to design drug reservoirs capable of both suppressing drug leakage below the transition temperature and accelerating drug release above it. Dynamic molecular binding sites were created by molecular imprinting that used 4,4'-diaminodiphenyl sulfone (dapsone) as the model drug, ß-cyclodextrin (CD) as the ligand, and N-isopropylacrylamide as the primary monomer. The molecularly imprinted (MIP) and nonimprinted (NIP) hydrogels with CD ligands, as well as the poly(N-isopropylacrylamide) (PNIPAAm) hydrogels without CD ligands, drastically shrunk above their transition temperature because of the PNIPAAm major chains changing conformation from a hydrophilic random coil to a hydrophobic globule as temperature increased. Because the MIP hydrogel has dynamic molecular binding sites, it absorbs a larger amount of dapsone than the NIP hydrogels in an aqueous solution below the transition temperature. The amount of dapsone adsorbed into the MIP hydrogel significantly decreased with increasing temperatures above 37 °C, despite the fact that the hydrophobic interaction between the polymer chains and dapsone became strong. The decrease in dapsone adsorption capability of the MIP hydrogel is due to a conformational change from a swollen to a shrunken state as temperature increases. The MIP hydrogel suppressed drug leakage below its transition temperature due to the high binding capacity of dynamic binding sites, but accelerated the drug release above its transition temperature due to the collapse of dynamic molecular binding sites, in contrast to the drug release behavior of general PNIPAAm-based hydrogels. Thus, the thermoresponsive MIP hydrogels with dynamic molecular binding sites regulated drug release in response to a change in temperature.

Photoresponsive Gelation of Four-Armed Poly(ethylene glycol) with Photodimerizable Groups.

Standard hydrogels prepared by free radical polymerization (FRP) have heterogeneous structures with a wide mesh size distribution, which affect their mechanical and separation properties. Recent research has identified four-armed poly(ethylene glycol) (tetra-PEG) as a solution to this problem. tetra-PEG gels with a homogeneous network can be prepared and applied as high-strength gels and cell-culture substrates by reacting two types of tetra-PEG with different reactive groups at the ends. In this study, we report a photoresponsive tetra-PEG that undergoes a phase transition from a sol to a gel state in response to light. tetra-PEGs containing cinnamoyl and maleimide groups at the ends of the four-armed chains were found to gel when exposed to light. The effects of polymer concentration and light irradiation time on the gelation of tetra-PEG containing photodimerization groups were investigated. The results showed that the elastic modulus of the gel increased with the increase in the light irradiation time.

Photoresponsive behaviour of zwitterionic polymer particles with photodimerizable groups on their surfaces.

Polymer particles with precise diameters have been used as building blocks for fabricating well-defined and nanostructured materials. Polymer particles as building blocks for medical applications require both easily spatiotemporal manipulation and good biocompatibility. In this study, we designed zwitterionic polymer particles with photodimerizable groups on their surfaces and used ultraviolet (UV) light irradiation to photo-assemble them in aqueous media. After synthesizing zwitterionic polymer particles with diameters ranging from 100-200 nm via soap-free emulsion polymerization, maleimide moieties as photodimerizable groups were introduced onto the particle surfaces. UV light irradiation to an aqueous dispersion of zwitterionic polymer particles with photodimerizable groups induced their photo-assembling because interparticle bonding forms by photodimerization of the photodimerizable groups on the particle surfaces. The zwitterionic surface of their particle-assembled films effectively suppressed protein adsorption, cell adhesion, and platelet adhesion. The photoresponsive behaviour and bioinert surface of the zwitterionic polymer particles with photodimerizable groups indicate that they have several potential applications as bioinert building blocks for designing well-defined and nanostructured biomaterials used in biosensors, bioseparation and cell culture, and for modifying and repairing biomaterial surfaces in situ.

Weakly Acidic pH and Reduction Dual Stimuli-Responsive Gel Particles.

This paper reports the facile preparation of dual stimuli-responsive gel particles that simultaneously respond to weakly acidic and reducing stimuli and the application of these gel particles as a drug delivery carrier. The dual stimuli-responsive gel particles composed of a pH-responsive polymer network cross-linked with reduction stimuli-responsive disulfide cross-links, and biocompatible poly(ethylene glycol) cross-links were prepared by soap-free emulsion polymerization. The resulting gel particles were colloidally stable at physiological ionic strength and had a diameter of approximately 200 nm with a narrow size distribution. The resulting gel particles slightly swelled in an acidic environment. On the other hand, the gel particles drastically swelled under simultaneous weakly acidic and reducing conditions because of the ionization of tertiary amino groups in the gel network and a decrease in the cross-linking density resulting from cleavage of the disulfide cross-links. When cells were treated with the gel particles, they were taken up by cells via the endocytosis pathway and distributed in the cytosol after endosomal escape by the proton sponge effect. In addition, a hydrophobic drug, doxorubicin (Dox), was loaded into the gel particles through hydrophobic interactions. Dox was released from the gel particles under weakly acidic and reducing conditions, while the Dox release was inhibited at neutral pH. The weakly acidic pH- and reduction stimuli-responsive release of Dox from gel particles was attributed to the drastic swelling of these particles. The fascinating properties of the dual stimuli-responsive gel particles suggest that they can provide a useful platform for designing intracellular drug delivery carriers.

Reductively Responsive Gel Capsules Prepared Using a Water-Soluble Zwitterionic Block Copolymer Emulsifier.

Utilizing the unique solubility of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), which is soluble in only water and alcohol, we synthesized a water-soluble block copolymer emulsifier composed of a hydrophilic PMPC block and an amphiphilic poly[oligo(ethylene glycol) methacrylate] (POEGMA) block via reversible addition-fragmentation chain transfer (RAFT) polymerization. Water-in-oil (W/O) emulsions were successfully formed in the presence of the resulting PMPC- b-POEGMA, which acted as a stabilizer of water droplets in a chloroform continuous phase because the PMPC and POEGMA blocks were distributed to the water and chloroform phases, respectively. Next, the amphiphilic poly[poly(ethylene glycol) methacrylate] (PPEGMA) gel layer, which contained bis(2-methacryloyl)oxyethyl disulfide as a reductively responsive cross-linker, was prepared by inverse miniemulsion periphery RAFT polymerization from the PMPC- b-POEGMA that stabilized the W/O emulsions. The resulting PPEGMA gel capsules were colloidally stable in not only chloroform but also water without additional hydrophilic surface modification. The drug-release behavior from the PPEGMA gel capsules in response to dithiothreitol (DTT), which is a reducing agent, was investigated using fluorescein-conjugated dextran (FITC-Dex) as a model drug. The FITC-Dex release rate from the gel capsules in a phosphate buffer solution (pH 7.4, 20 mM) with DTT was fast compared to that without DTT. The reductively responsive FITC-Dex release is attributed to the cleavage of disulfide bonds that act as cross-links in the PPEGMA gel layer. The fascinating properties of the PPEGMA gel capsules suggest that they can provide a useful platform for designing drug carriers for protein and gene delivery and nanobioreactors.

Preparation of molecule-responsive microsized hydrogels via photopolymerization for smart microchannel microvalves.

Microdevices designed for practical environmental pollution monitoring need to detect specific pollutants such as dioxins. Bisphenol A (BPA) has been widely used as a monomer for the synthesis of polycarbonate and epoxy resins. However, the recent discovery of its high potential ability to disrupt human endocrine systems has made the development of smart systems and microdevices for its detection and removal necessary. Molecule-responsive microsized hydrogels with ß-cycrodextrin (ß-CD) as ligands are prepared by photopolymerization using a fluorescence microscope. The molecule-responsive micro-hydrogels show ultra-quick shrinkage in response to target BPA. Furthermore, the flow rate of a microchannel is autonomously regulated by the molecule-responsive shrinking of their hydrogels as smart microvalves.

Target molecule-responsive hydrogels designed via molecular imprinting using bisphenol A as a template.

Target molecule-responsive hydrogels with ß-cyclodextrin (ß-CD) were prepared via molecular imprinting using bisphenol A (BPA) as a template. BPA-imprinted hydrogels showed greater shrinkage than non-imprinted hydrogels because CD ligands arranged at suitable positions formed CD-BPA-CD complexes that acted as crosslinks.

Synthesis of glucose-responsive bioconjugated gel particles using surfactant-free emulsion polymerization.

Bioconjugated gel particles that have complexes composed of lectin concanavalin A (ConA) and 2-glucosyloxyethyl methacrylate (GEMA) were synthesized by the surfactant-free emulsion copolymerization of N,N-diethylaminoethyl methacrylate (DEAEMA), poly(ethylene glycol) dimethacrylate (PEGDMA), GEMA, and modified-ConA with polymerizable groups. The resultant gel particles having GEMA-ConA complexes (GEMA-ConA gel particles) were colloidally stable in a phosphate buffer solution and had a diameter of approximately 750nm. Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS) measurements implied that GEMA-ConA gel particles have core-shell structures consisting of a hydrophobic core of DEAEMA and a hydrophilic shell of GEMA and PEGDMA containing ConA. GEMA-ConA gel particles underwent a change in size in response to glucose in a phosphate buffer solution. The swelling ratio of GEMA-ConA gel particles gradually increased with an increase in the glucose concentration. On the other hand, the swelling ratio of GEMA-ConA gel particles remained unchanged in a phosphate buffer solution containing galactose. The glucose-responsive swelling of GEMA-ConA gel particles was induced by the dissociation of GEMA-ConA complexes acting as reversible cross-links, because free glucose behaved as an inhibitor of GEMA-ConA complexes. These results indicate that GEMA-ConA gel particles can recognize glucose selectively and undergo changes in size in response to the glucose concentration. The smart functions of glucose-responsive gel particles can provide tools for constructing self-regulated drug delivery systems and sensor systems useful for treating diabetes.

Effect of enzyme modification by well-defined multi-armed poly(ethylene glycol) synthesized using polyamidoamine dendron.

Egg white lysozyme was chemically modified by PEGylated PAMAM 1st, 2nd and 3rd generation dendrons, which had 2, 4 and 8 PEG arms, respectively. The number of PEG chains introduced to the lysozyme molecule drastically increased with an increase in dendron generation, although the number of PEGylated PAMAM dendrons introduced decreased due to steric repulsion. The lytic activity of lysozyme to Micrococcus luteus cells was effectively inhibited by conjugating PEGylated PAMAM dendron to the lysozyme, indicating steric stabilization of PEG chains at the surface of lysozyme molecule. In addition, the enzymatic reaction of the lysozyme with oligosaccharide substrate was apparently accelerated by a substrate condensation effect due to the multi-armed structure of PEG.

Self-assembled nano-bioreactor from block ionomers with elevated and stabilized enzymatic function.

Core-cross-linked polyion complex (PIC) micelles entrapping trypsin in the core were prepared by mixing trypsin and poly(ethylene glycol)-block-poly(alpha,beta-aspartic acid) in aqueous medium, followed by the introduction of glutaraldehyde cross-linkages. Trypsin incorporated into the core-cross-linked micelles showed high storage stabilities, and the initial enzymatic activity of trypsin was maintained even after standing for one week at ambient temperature. Further, stable compartmentalization of trypsin into the core-cross-linked micelles led to a unique modulation in the enzymatic functions including an improved thermal tolerability with an increased maximum reaction rate compared to native trypsin.

Effect of polycarboxylate blocks on the amidase activity of trypsin through complexation with PEG/polycarboxylate block ionomers.

The amidase reaction of trypsin, which is a member of the serine proteinase family, is accelerated by its complexation with block ionomers containing a polycarboxylate block, such as PEG-PAA, PEG-PGA, or PEG-PMA. PEG-PAA and PEG-PGA had similar effects, causing an increase in the k(cat) value and a shift in the pH profile to a lower pH region. On the other hand, PEG-PMA showed not only an increase in the k(cat) value, but also a decrease in the activation energy; however, there was no shift in the pH dependence of the initial reaction rate. Such differences might be induced by the difference in pK(a) values of the polycarboxylate block in block ionomers.

Acceleration of enzymatic reaction of trypsin through the formation of water-soluble complexes with poly(ethylene glycol)-block-poly(alpha,beta-aspartic acid).

The amidase activity of bovine pancreas trypsin in water-soluble complexes with poly(ethylene glycol)-block-poly(alpha,beta-aspartic acid) (PEG-PAA) was evaluated by a colorimetric assay using L-lysine p-nitroanilide as a substrate. The enzymatic reaction of trypsin was accelerated through the complexation with PEG-PAA. By determining the kinetic parameters of the enzymatic reaction of trypsin, it was confirmed that the catalytic rate constant of the complexed trypsin was 15 times higher than that of the native trypsin. From the evaluation of pH dependence of initial reaction rate, it was indicated that this acceleration was induced by a stabilization of the imidazolium ion of the His residue in the catalytic site, the Asp-His-Ser triad, of trypsin due to the Asp units of PEG-PAA. The hydrogen bonded Asp-His pairs are critical constituents in several key enzymatic reactions including serine protease and apurinic endonucleases, and it was expected that the acceleration of the catalytic reaction might occur for other enzymes by the formation of water-soluble complexes with PEG-PAA.