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Nonconventional stimuli-responsive luminescent polymers without aromatic units have garnered considerable attention. In this study, luminescent ampholytic block copolymer (BCP) and random copolymer (RCP) consisting of nonconjugated vinyl amine (VAm) and N -acryloyl-L-threonine (AThrOH) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization and subsequent deprotection. The ampholytic BCP and RCP display concentration-enhanced emissions, which are apparently higher than those of the VAm homopolymer and polyion complex, and wavelength-dependent emissions, thus validating clusterization-triggered emission (CTE). The intrinsic photoluminescence properties of the primary amine-containing ampholytic copolymers and corresponding polyion complexes were investigated in aqueous solution in response to the change in pH. Two noncovalent interactions, which involve electrostatic interactions between cationic VAm and anionic AThrOH units and hydrogen bonds (e.g., the amino group in VAm/hydroxyl and amide groups in AThrOH), contribute to the achievement of unique self-assembled structures and stimuli-responsive and fluorescent properties of VAm-containing BCP and RCP, which were verified by dynamic light scattering, circular dichroism, and fluorescence measurements. The ability of the copolymers to form clusterized states of the VAm unit can be governed by the comonomer sequence and external stimuli (e.g., pH change, the addition of salt and urea), leading to the manipulation of the assembled structures with CTE features. [Display omitted] • Luminescent ampholytic block and random copolymers without aromatic units were developed. • Copolymers consisting of vinyl amine (VAm) and N -acryloyl-L-threonine were synthesized by RAFT polymerization. • The ampholytic copolymers exhibited concentration-enhanced emissions and wavelength-dependent emissions. • Unique assembled structures and VAm-based clusterization-triggered emission (CTE) were confirmed. • The comonomer sequence and external stimuli led to the manipulation of the assembled structures with CTE features. [ABSTRACT FROM AUTHOR]

Developing delivery vehicles that achieve drug accumulation in the liver and transferability into hepatic stellate cells (HSCs) across the liver sinusoidal endothelium is essential to establish a treatment for hepatic fibrosis. We previously developed hyaluronic acid (HA)-coated polymeric micelles that exhibited affinity to liver sinusoidal endothelial cells. HA-coated micelles possess a core-shell structure of self-assembled biodegradable poly(l-lysine)- b -poly(lactic acid) AB-diblock copolymer (PLys + - b -PLLA), and its exterior is coated with HA through polyion complex formation via electrostatic interaction between anionic HAs and cationic PLys segments. In this study, we prepared HA-coated micelles entrapping olmesartan medoxomil (OLM), an anti-fibrotic drug, and evaluated their possibility as drug delivery vehicles. HA-coated micelles exhibited specific cellular uptake into LX-2 cells (human HSC line) in vitro. In vivo imaging analysis after intravenous ( i.v .) injection of HA-coated micelles into mice revealed that the micelles exhibited high accumulation in the liver. Observation of mouse liver tissue sections suggested that HA-coated micelles were distributed in liver tissue. Furthermore, i.v . injection of HA-coated micelles entrapping OLM showed a remarkable anti-fibrotic effect against the liver cirrhosis mouse model. Therefore, HA-coated micelles are promising candidates as drug delivery vehicles for the clinical management of liver fibrosis.

Peptide-conjugated polysaccharide matrices using bioactive laminin-derived peptides are useful biomaterials for tissue and cell engineering. Here, we demonstrate an easy handling preparation method for peptide-polysaccharide matrices using polyion complex with both alginate and chitosan. First, aldehyde-alginate was synthesized by oxidization of alginate using NaIO4 , and then, reacted with Cys-peptides. Next, the peptide-alginate solution was added to a chitosan-coated plate, and the peptide-polyion complex matrices (peptide-PCMs) were prepared. The peptide-PCMs using an integrin αvβ3-binding peptide (A99a: ALRGDN, mouse laminin α1 chain 1145-1150) and an integrin α2β1-binding peptide (EF1XmR: RLQLQEGRLHFXFD, X = Nle, mouse laminin α1 chain 2751-2763) showed strong cell attachment activity in a dose-dependent manner. When we examined the effect of various spacers on the biological activity of A99a-PCM, hydrophobic and long spacers enhanced the cell attachment activity. Further, the A99a-PCM with the spacers strongly promoted neurite outgrowth. The polyion complex method is an easy way to obtain insolubilized matrix and is widely applicable for various polysaccharides. The peptide-PCM is useful as a biomaterial for cell and tissue engineering. [ABSTRACT FROM AUTHOR]

The rapid developments of tough hydrogels have promoted the applications of this kind of soft materials in loading bearing systems. However, tough gels usually have poor processibility, which is crucial for the construction of complex structures with gels. In this paper, we demonstrate the processing of tough polyion complex (PIC) hydrogels by simple compression moulding or extruding, which relies on the distinct strength of ionic bonds during and after the processing. The PIC precipitates formed by mixing the solutions of polycation and polyanion, poly(3-(methacryloylamino)propyl-trimethylammonium chloride) and poly(sodium p-styrenesulfonate), are plasticized by saline solution with selected concentration. These raw materials, initially weak and viscoelastic, are easily processed into different shapes. After swelling the as-prepared gels in water to dialyze out the salt and counterions of PIC, tough equilibrated gels are obtained with the imposed shapes during processing. These gels with 50–70 wt% water show good mechanical properties, with tensile fracture stress, fracture strain and tearing fracture energy being 3.7 MPa, 700% and 8 × 10 3 J/m 2 , respectively. These mechanical properties can be effectively tailored by tuning the charge ratio of PIC. However, the concentration of saline water has negligible influence on the mechanical properties of final equilibrated gels. The resultant PIC gels also exhibit stimuli-triggered healing properties owing to the dynamic and reversible nature of the ionic bonds. This study should promote the applications of tough PIC gels in structural elements of soft actuators and synthetic tissues. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate a library of poly- l -lysine (PLL)-graft (g)-polyethylene glycol (PEG) copolymers for the ability to encapsulate effectively a model protein, bovine serum albumin (BSA), and to characterize the stability and protein function of the resulting nanoparticle. A library of nine grafted copolymers was produced by varying PLL molecular weight and PEG grafting ratio. Electrostatic self-assembly of the protein and the grafted copolymer drove encapsulation. The formation of protein/polymer nanoparticles with a core/shell structure was confirmed using PAGE, dynamic light scattering, and electron microscopy. Encapsulation of the BSA into nanoparticles was strongly dependent on the copolymer-to-protein mass ratio, PEG grafting ratio, and PLL molecular weight. A copolymer-to-protein mass ratio of 7:1 and higher was generally required for high levels of encapsulation, and under these conditions, no loss of protein activity was observed. Copolymer characteristics also influenced nanoparticle resistance to polyanions and protease degradation. The results indicate that a copolymer of 15–30 kDa PLL, with a PEG grafting ratio of 10:1, is most promising for protein delivery. [ABSTRACT FROM AUTHOR]

A polymer film composed of a mixture of chitosan (Ch) and carboxymethyl cellulose sodium salt (CMC) nanofibers was deposited on a glass surface. The thin film of the Ch–CMC mixture obtained was stable, and fibroblast adhesion to the film was lowest when the weight ratio of Ch to CMC was 4:6. The ζ-potential and contact angle of the mixture film indicated that a polyion complex of Ch and CMC was formed. The mechanical strength of the film composed of Ch–CMC nanofiber complexes was much higher than that of the film composed of Ch–water-soluble CMC complexes (non-nanofiber), likely because the entanglement of nanofibers was enhanced by electrostatic attractions. These results indicate that the charge-neutralized nanofiber film was highly effective in suppressing cell adhesion and therefore is a promising material for biomedical applications. [ABSTRACT FROM AUTHOR]

A strategy for constructing polyion complex vesicles (PICsomes) with asymmetric structure is described. Poly(methylacrylic acid)-block-poly(N-isopropylacrylamide) modified gold nanoparticles (PMAA-b-PNIPAm-@-Au NPs) were prepared and then assembled with poly(ethylene glycol)-block-poly[1-methyl-3-(2-methacryloyloxy propylimidazolium bromine)] (PEG-b-PMMPImB) via polyion complex of PMMA and PMMPImB. After removing the Au NPs template, asymmetric PICsomes composed of a PNIPAm inner-shell, PIC wall, and PEG outer-corona were obtained. These PICsomes have low protein absorption and thermally tunable permeability, provided by the PEG outer-corona and the PNIPAm inner-shell, respectively. Moreover, PICsome size can be tailored by using templates of predetermined sizes. This novel strategy for constructing asymmetric PICsomes with well-defined properties and controllable size is valuable for applications such as drug delivery, catalysis and monitoring of chemical reactions, and biomimetics.

Humic substances (HS) coexisting with colloidal particles are inevitable in water bodies. Since the cationic flocculant used for flocculation treatment in such water bodies interacts electrostatically with HS and colloidal particles, the efficiency of the flocculant tends to be lower than in water bodies containing only colloidal particles. The colloidal flocculation mechanism by polycation with low charge density is dominated by bridging effects rather than charge neutralization effects. Furthermore, the polyionic complex formation of low charge density polycations with HS is not stoichiometric, based on the oppositely charged groups. Therefore, it was unclear how HS affects the flocculation of colloidal particles by polycation with low charge density. In this study, the effects of two naturally occurring HS and two synthetic polyanions on the flocculation behavior of negatively charged polystyrene latex (PSL) particles induced by polycationic flocculant with low charge density (4 %) were investigated under standardized mixed fluid conditions. Considering the flocculation inhibition effect in terms of the molar concentration ratio of flocculant-derived cations to polyanion-derived anions, it was found that polyanions less inhibit the flocculation of PSL particles by flocculant with low charge density compared to flocculant with high charge density. The relationship between the degree of inhibition of flocculation and the affinity of polyanions for polycations obtained from electrophoretic mobility experiments was verified, and the effectiveness of using low charge density polycations as particle flocculants in water bodies containing particles and HS was discussed. [Display omitted] • Polycationic flocculants were used to flocculate anionic colloidal particles. • Colloidal flocculation is inhibited by synthetic and naturally occurring polyanions. • Flocculation inhibition is due to the interaction between flocculant and polyanion. • Flocculation inhibition was suppressed by polycation with lower charge density. [ABSTRACT FROM AUTHOR]

Free-standing films of natural polysaccharides were prepared using hot press techniques. Polyion complexes (PICs) made of acidic polysaccharides such as chondroitin sulfate C and chitosan were formed into thin films by hot pressing. The times needed to conduct the process from PIC formation using polysaccharide solutions of two kinds to obtaining films were 30 min or less under appropriate conditions. The resulting films swelled in distilled water to some degree but were not dissolved despite being made of water-soluble polysaccharides. Contact angle measurements supported dense surface structure of the films because of the effects of hot pressing. The films had sufficient mechanical properties to be used as structural materials. Polysaccharide species and film preparation processes affected some film properties. [ABSTRACT FROM AUTHOR]

Ordered assembly of imogolite clay nanotubes was achieved by the spatiotemporal regulation of imogolite complex formation using an organic polyelectrolyte. In a confined reaction space, imogolites formed assemblies with anisotropic birefringence and distinct optical texture under uni-directional diffusion. In assemblies with anisotropic birefringence, imogolite nanotubes uniformly aligned along the longitudinal axis of the assemblies. The ordered structure of imogolites drastically changed with the size of the reaction space and the concentration of components that control a number of nuclei in the assembly. The perfectly rigid rod-like nature of imogolite clay nanotubes induces their ordered alignment. [ABSTRACT FROM AUTHOR]

An amperometric urea biosensor based on urease and metal catalysts (Pt and Rh) has been synthesized on a multiwalled carbon nanotube (MWCNT)-modified ITO glass. A sequential coating of the metal catalysts and urease over the surface of the MWCNT-modified ITO glass was adopted for the electrode preparation by entrapment with a polyion complex (PIC). The activity of the immobilized enzyme for urea hydrolysis and the metal catalysts for the electrochemical oxidation of the ammonia generated during the enzymatic reaction were investigated. The electrochemical performance of the bioelectrode was characterized by a cyclic voltammetry technique. The sensor exhibited a linear amperometric response to urea concentration ranging from 0.05 mM to 20 mM, with a linear correlation coefficient of 0.995. A sensitivity of 1.7 μA mM −1 cm −2 and a response time of approximately 10 s were achieved for the hybrid electrode. The biosensor retained half of its initial activity after 20 days of storage under ambient conditions. The urea sensor employing an enzyme and metal catalysts exhibited excellent electroactivity and sensor efficiency. [ABSTRACT FROM AUTHOR]

A polyion complex nano-prodrug based on the complexation of the ionomer of poly(lactic acid-co-malic acid)-block-polyethylene glycol [Poly(LA-co-MA)-b-PEG] with doxorubicin (DOX) was developed. The ionomer was prepared by a direct polycondensation of d, l-lactic acid (LA), l-malic acid (MA), and monomethyl polyethylene glycol (PEG) using stannous chloride (SnCl) as the catalyst. The nanoparticles were formed through electrostatic interactions between the side carboxyl groups of MA units in the ionomer and amino groups of DOX. The nanoparticle possessed an amphiphilic structure with a hydrophobic core of the complexed DOX and Poly(LA-co-MA) and a hydrophilic shell of PEG. The nanoparticle solution was stable, and the particle sizes were in the range of 110-140 nm. The DOX was loaded as a prodrug with loading rate as high as 18.2 %. The drug release could be controlled, showing responsiveness of acids and ionic strength. The cumulative release was as high as 94 %. The nanoparticles could be potentially used as anti-cancer drug vehicles. [ABSTRACT FROM AUTHOR]

Cationic flocculants with varying branching structure sometimes exert dramatically different flocculating abilities on oppositely charged particles. However, their flocculation mechanisms and performances under aqueous conditions in the presence of oppositely charged colloidal particles and polyanions, which commonly exist in natural systems, have not yet been fully elucidated. In this work, three cationic flocculants with different branches per molecule and similar charge densities were used to flocculate negatively charged colloidal particles coexisting with synthetic and naturally occurring polyanions. The electrophoretic mobility of the polymer-coated particles revealed that the branched flocculants required a higher optimum dosage than the linear ones. Under all tested conditions, flocculation was remarkably enhanced by increasing the number of branches in the flocculant. Electrophoretic titrations showed that the interactions between the flocculants and the polyanions to form a polyion complex (PIC) were mainly driven by electrostatic attractions. Hence, the number of branches had no significant effect on PIC formation. These results suggest that unlike the PIC formed by flexible linear flocculants that adopt a flat conformation upon adsorption onto the particle surface, the rigid branched-polyanion PIC tends to retain its shape. This effect is due to the presence of branches that are less prone to undergo relaxation. As a result, a thick adsorbed layer was formed on the particle surface, which improved the effective collision between particles and facilitated bridging flocculation. [Display omitted] • Three cationic flocculants were used to flocculate negatively charged colloidal particles. • These particles coexisted with synthetic and naturally occurring polyanions. • Flocculation was enhanced by increasing the degree of flocculant branching. • A thick adsorbed layer was formed on the particle surface. • This promoted collisions between particles and facilitated bridging flocculation. [ABSTRACT FROM AUTHOR]

Polyion complex (PIC) layers are formed via self-assemble ion pairing by alternately placing polycation/polyanion solutions on platinum electrodes. Their molecular sieving behavior for electrochemically reactive species through the layers is examined by electrochemical methods. Different molecular-sieve sizes are achieved by the selection of polycations with different intramolecular distances of neighboring cationic groups. Amperometric glucose sensing electrodes are fabricated by immobilizing glucose oxidase in a PIC double-layer. The proper double-layer configuration is efficient to improve the glucose response, blocking interferents due to the molecular sieving effect. [ABSTRACT FROM AUTHOR]

Natural polysaccharides are promising candidates for the component of polymer materials for sustainable societies. Here, the preparation of composite films using high- and low-molecular weight (MW) of hyaluronic acid (H-HYA and L-HYA), carboxymethylated HYA (CM-HYA), and high- and low-MW of chitosan (H–CHI and L-CHI) was performed to clarify the effects of the polysaccharide species on formability, mechanical properties, and water-responsive properties of the resulting films. The films prepared using CM-HYA and H–CHI (CM-HYA/H–CHI films) exhibited the highest maximum stress due to more electrostatic interactions between COO− in CM-HYA and NH 3 + in H–CHI. Swelling ratio of CM-HYA/H–CHI films was the lowest both in water and phosphate buffer saline (PBS). Meanwhile, CM-HYA/H–CHI films exhibited the highest moisture absorption ratio and moisture retention capacities, indicating water absorption ability of CM-HYA could be maintained even in the film state. Accordingly, CM-HYA/H–CHI films may be advantageous for applications such as moisture-retaining sheets and biomaterials. [Display omitted] • Composite films with hyaluronic acid and chitosan were successfully prepared. • Effects of chemical species on these film properties are discussed. • Carboxymethylated hyaluronic acid (CM-HYA) improved the mechanical properties. • CM-HYA provided the highest moisture absorption ratio and retention capacity. • The composite films may become a candidate for moisturizing sheets. [ABSTRACT FROM AUTHOR]

Abstract: Oppositely charged polyelectrolytes can be used to form various types of self-assembled structures directed by multivalent ionic interactions. The supramolecular architectures that result are often referred to as polyion complexes (PICs). Synthetic polyion complexes are exciting candidates for biomedical applications. Their self-assembly capabilities give rise to hierarchical mesoscopic platforms such as micelles, membranes, and capsules through simple mixing processes. These complexes are also ideal candidates for the transport and delivery of biological agents since biomolecules, such as DNA and proteins can be easily incorporated through ionic interactions. PICs have therefore found use in drug delivery, diagnostics, gene therapy, biosensors and microreactors. In this paper, we briefly review examples of polymeric supramolecular assemblies based on multivalent ionic interactions for biomedical applications. [Copyright &y& Elsevier]

Alginic acid from seaweed and chitosan derived from shrimp and crab shells are well known as abundant biopolymers of marine origin. Alginic acid as a polyanion and chitosan as a polycation produce a polyelectrolyte complex (PIC) by ionic crosslinking. So far, PIC has been prepared by alternate lamination or casting methods. In this study, a novel continuous preparation method of PIC was demonstrated with an extruder and a hot press. It was confirmed that homogeneous PIC sheets were prepared conveniently. Moreover, by adding various plasticizers it was shown that mechanical properties of PIC were controllable in a range of hard and soft materials. [ABSTRACT FROM AUTHOR]

We developed processes to obtain water-insoluble fibers from polyion complexes (PIC) of chondroitin sulfate C (CS) and chitosan (CHI) by utilizing interface-spinning methods. A CS solution was gently placed on a CHI solution, which resulted in formation of films made of PIC at the solution interfaces. Fibers were spun by withdrawing the films from the interfaces, then dried by passing through an acetone bath and finally rolled up. We evaluated the morphology and strength of the prepared fibers. Several meters-long CS/CHI composite fibers having several tens of micrometers diameter were successfully obtained through this process. Interestingly, it was found that tensile strength increased as the molecular weight of CHI increased. Swelling-stretching treatment made these fibers denser and stronger than before treatment. The experimental results revealed that these fibers made of CS/CHI had mechanical properties sufficient for structural materials. [ABSTRACT FROM AUTHOR]

Abstract: Reactive oxygen species (ROS) scavengers have not been widely used for treatment of local inflammatory reactions such as arthritis and periodontal disease because they are rapidly eliminated from the inflamed site, which results in a low therapeutic effect. Therefore, to enhance the local retention time of ROS scavengers, we developed a redox-active injectable gel (RIG) system by using poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene]-b-poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PMNT-PEG-PMNT) triblock copolymer, which possesses ROS scavenging nitroxide radicals as side chains of the PMNT segment. Cationic PMNT segment in PMNT-PEG-PMNT forms polyion complexes with anionic poly(acrylic acid) (PAAc) to form a flower-like micelle (ca. 79nm), which exhibits in situ thermo-irreversible gelation under physiological conditions. We confirmed the prolonged site-specific retention time of RIG by performing in vivo noninvasive electron spin resonance imaging and quantitative evaluation. In contrast to low-molecular-weight nitroxide radical compounds that disappeared from injection sites in less than 1h after subcutaneous injection, 40% of the RIG remained even at 3days. We also found that RIG inhibits neutrophil infiltration and cytokine production, which leads to suppression of hyperalgesia. These findings indicate the potential of RIG as an innovative approach for treatment of local inflammation. [Copyright &y& Elsevier]

Abstract: Janus-like co-assemblies are expected if non-centrosymmetric host macromolecules are used as precursors. As a natural choice, bis-hydrophilic ionic/non-ionic macromolecules can be complexed with linear homopolyelectrolytes, generating interpolyelectrolyte complexes (IPECs). At the same time, complexation-induced aggregation could result in centrosymmetric species, thereby masking the original non-centrosymmetric character of the IPECs. Thus, water-soluble IPECs would possess Janus-like character if their particles would contain only one non-centrosymmetric host in a co-assembled entity. This goal can be achieved by using miktoarm stars, as star-shaped polyelectrolytes provide higher tendency toward the formation of molecularly-dispersed IPECs. Therefore, water-soluble IPECs with different charge-to-charge ratios were prepared. An excess of miktoarm stars possessing ∼3 polycation arms (quaternized poly(dimethylaminoethyl methacrylate) PDMAEMAQ) and 1 poly(ethylene oxide) PEO arm was mixed with poly(styrene sulfonate) PSS. Then, sedimentation velocity analysis was performed by help of Analytical Ultracentrifugation (AUC). These measurements were supplemented by dynamic light scattering, density measurements and 2D NOESY NMR to determine the molar mass of the co-assembled structures and to learn about the internal structure. As shown by AUC, the IPECs consist of one star per co-assembled structure, when having excess star as host. At the same time, the non-centrosymmetric character of miktoarm stars is kept, leading to Janus-like IPECs. [Copyright &y& Elsevier]

Polyion complex (PIC) micelles were spontaneously formed in aqueous solutions through electrostatic interaction between two oppositely charged block copolymers, poly( N-isopropylacrylamide) -b-poly(L-glutamic acid) and poly( N-isopropylacrylamide)- b-poly(L-lysine). Their controlled synthesis was achieved via the ring opening polymerization of N-carboxyanhydrides (NCA), γ-benzyloxycarbonyl-L-lysine (Lys(Z)-NCA) or γ-benzyl-L-glutamate (BLG-NCA) with amino-terminated poly( N-isopropylacrylamide) macroinitiator and the subsequent deprotection reaction. The formation of PIC micelles was confirmed by dynamic light scattering and transmission electron microscopy. Turbidimetric characterization suggested that the formed PIC micelles had a concentration-dependent thermosensitivity and their phase transition behaviors could be easily adjusted either by the block length of coplymers or the concentration of micelles. [ABSTRACT FROM AUTHOR]

Abstract: Here, we synthesized dextrans modified with trivalent cationic or anionic groups. Aqueous solutions of the cationic and anionic dextrans were then mixed resulting in the formation of polyion complex nanogels (PIC-NGs), which have physically crosslinked salt bridges formed between the cationic and anionic groups. To prepare PIC-NGs in high yield, the content of ionic groups in the cationic and anionic dextrans should be low to avoid interparticle salt bridge formation. The structure of the PIC-NGs is easily affected by the ionic strength of the solution because of shielding of the charges in the ionic groups. However, the conversion of a small amount of the physical crosslinks to covalent crosslinks significantly improved the stability of the PIC-NGs. The covalent crosslinking also stabilized the PIC-NGs against pH change, which will destabilize the salt bridges. These results indicated that the conversion of the small amount of physical crosslinks to covalent crosslinks stabilized the other salt bridges. [Copyright &y& Elsevier]

Abstract: Recently, colloidal carrier systems have been receiving much attention in the field of drug targeting because of their high loading capacity for drugs as well as their unique disposition characteristics in the body. This paper highlights the utility of polymeric micelles formed through the multimolecular assembly of block copolymers as novel core–shell typed colloidal carriers for drug and gene targeting. The process of micellization in aqueous milieu is described in detail based on differences in the driving force of core segregation, including hydrophobic interaction, electrostatic interaction, metal complexation, and hydrogen bonding of constituent block copolymers. The segregated core embedded in the hydrophilic palisade is shown to function as a reservoir for genes, enzymes, and a variety of drugs with diverse characteristics. Functionalization of the outer surface of the polymeric micelle to modify its physicochemical and biological properties is reviewed from the standpoint of designing micellar carrier systems for receptor-mediated drug delivery. Further, the distribution of polymeric micelles is described to demonstrate their long-circulating characteristics and significant tumor accumulation, emphasizing their promising utility in tumor-targeting therapy. As an important perspective on carrier systems based on polymeric micelles, their feasibility as non-viral gene vectors is also summarized in this review article. [Copyright &y& Elsevier]

Abstract: A new family of block ionomer complexes (BIC) formed by poly(ethylene glycol)-block-poly(4-vinylbenzylphosphonate) (PEG-b-PVBP) and various cationic surfactants was prepared and characterized. These complexes spontaneously self-assembled in aqueous solutions into particles with average size of 40–60nm and remained soluble over the entire range of the compositions of the mixtures including stoichiometric electroneutral complexes. Solution behavior and physicochemical properties of such BIC were very sensitive to the structure of cationic surfactants. Furthermore, such complexation was used for incorporation of cationic anti-cancer drug, doxorubicin (DOX), into the core of BIC with high loading capacity and efficiency. The DOX/PEG-b-PVBP BIC also displayed high stability against dilution, changes in ionic strength. Furthermore, DOX release at the extracellular pH of DOX/PEG-b-PVBP BIC was slow. It was greatly increased at the acidic pH mimicking the endosomal/lysosomal environment. Confocal fluorescence microscopy using live MCF-7 breast cancer cells suggested that DOX/PEG-b-PVBP BICs are transported to lysosomes. Subsequently, the drugs are released and exert cytotoxic effect killing these cancer cells. These findings indicate that the obtained complexes can be attractive candidates for delivery of cationic drugs to tumors. [Copyright &y& Elsevier]

All- trans-retinoic acids (ATRA) are ionically complexed with cationic polyelectrolytes containing tertiary amines and self-assembled into nanoscale colloidal structures. Poly(2-(dimethylamino)ethyl methacrylate) grafted with polyethylene glycol, poly(DMAEMA- g-PEG), is used as a double hydrophilic, cationic polyelectrolyte. The polyion/ATRA complexes are formed by adding ATRA in dimethyl sulfoxide into aqueous solution of poly(DMAEMA- g-PEG). This complexation effectively suppresses the formation of undesirable drug crystallites and produces stable colloidal nanostructures having a hydrodynamic diameter of about 15 nm at a neutral pH. However, as the pH decreases below about 6, they undergo dramatic structural change into large aggregates of about 250 nm in diameter presumably due to the dissociation of ATRA from the polyelectrolyte. We expect that this pH-sensitive response of the polyion/ATRA complexes is useful for intracellular translocation at a neutral pH followed by the endosomal escape of ATRA in an acidic condition. [ABSTRACT FROM AUTHOR]

Abstract: Here, we report the fluorometric detection of protein kinase Cα (PKCα) activity in a cancerous cell lysate using a polyion complex (PIC) composed of a quencher (BHQ3)-modified chondroitin sulfate [CS(X)] and a dendrimer modified with a cationic peptide substrate (FKKQGSFAKKK-NH2) and a near infrared (NIR) fluorophore (Cy5.5) (polymer 1). When polymer 1 formed the PIC with CS(X) through electrostatic interactions, the NIR fluorescence was quenched effectively via Förster resonance energy transfer (FRET) between Cy5.5 and BHQ3. However, this quenched fluorescence was recovered when the pendant peptides in polymer 1 were phosphorylated with PKCα due to the dissociation of the PIC. When PKCα was added to the PIC dispersion, a significant increase in fluorescence intensity was observed, whereas its fluorescence increase was inhibited with a PKCα inhibitor in a concentration-dependent manner. Furthermore, our PIC was robust enough to measure PKCα activity in a cancerous cellular lysate without purification. The PKCα-responsive PIC offers a simple, rapid, sensitive, and robust approach to detect PKCα activity in crude cellular lysates that would be suitable for drug screening formats and cancer diagnosis using crude cellular lysates. [Copyright &y& Elsevier]

Poly(2,2′-disulfonyl-4,4′-benzidine terephthalamide) (PBDT), a kind of liquid-crystalline (LC) molecule, has high molecular weight, negative charge and a semi-rigid structure. The aqueous solution of PBDT shows nematic liquid crystalline state above a critical PBDT concentration, C*, of 2 wt%-3wt%. Different from the flexible polyelectrolyte, PBDT shows a variety of self-assembling structures in aqueous solution with and without salt due to the semi-rigid nature and highly charged property. In addition, the hydrogels with ordered structure are developed by polymerizing a cationic monomer N-[3-( N,N-dimethylamino) propyl] acrylamide methyl chloride quarternary (DMAPAA-Q) in the presence of a small amount of PBDT below the C*. During the polymerization of cationic monomer, the polycations form a complex with semi-rigid PBDT through electrostatic interaction; these complexes self-assemble into ordered structures that are frozen in the hydrogel. Several different structures, including the anisotropic, dual network-like structure, and cylindrically symmetric structure, with various length scales from micrometer to millimeter, are observed. The hydrogels with ordered liquid crystalline assemblies and particular optical properties should promise applications in many fields, such as in bionics, tissue engineering, and mechano-optical sensors. [ABSTRACT FROM AUTHOR]

Abstract: The delivery of siRNA therapeutics owes its success to the development of carrier systems with high efficacy and minimum toxicity. Here, cationic polyaspartamide derivatives with a regulated number and spacing of positively charged amino groups in the side chain were prepared from a single platform polymer of poly(β-benzyl l-aspartate) to assess their availability as siRNA carriers through polyion complex (PIC) formation. These polymers have 1,2-diaminoethane, 1,3-diaminopropane, and N,N’-bis(2-aminoethyl)-1,2-diaminoethane moieties in the side chain, and are termed as PAsp(DET), PAsp(DPT), and PAsp(TEP), respectively. siRNA-loaded PICs stable in serum-containing media were formed from PAsp(TEP) and PAsp(DPT) with two positive charges in the side chain at pH 7.4, whereas no such stable PIC was obtained from PAsp(DET) with only a single charge in the side chain, suggesting facilitated multivalent interactions with siRNA molecules to increase the PIC stability. The PAsp(DPT) and PAsp(TEP) PICs stable in the serum-containing media underwent an appreciably enhanced uptake into cultured cells through endocytosis, and subsequently exerted effective endosomal escape for the significant silencing of target gene expression. Notably, PAsp(TEP) PIC displayed negligible cytotoxicity in sharp contrast to the highly toxic feature of PAsp(DPT) PIC. This cytotoxicity is apparently correlated with the minimal damage to the cytoplasmic membrane of cells exposed to PAsp(TEP) at pH 7.4 evidenced from the fluorescent dye (YO-PRO-1) permeation assay. There was, in turn, a significant increase in YO-PRO-1 permeability at endosomal pH of 5.5 for PAsp(TEP)-exposed cells, indicating that PAsp(TEP) exerts membrane damage in a pH-selective manner, and eventually facilitates the translocation of siRNA-loaded PIC from the acidic endosomal compartment into the cytoplasm for effective gene silencing without any severe toxicity at physiological conditions. This acidic pH modulated enhancement in membrane damage of PAsp(TEP) may be explained by an increased protonation of the arrayed amino groups in the side chain that strongly perturb the endosomal membrane integrity. Eventually, PAsp(TEP) with a side chain array of pH-sensitive amino groups was demonstrated to be a promising component for constructing siRNA carriers exerting effective gene silencing in a less toxic context. [Copyright &y& Elsevier]

Abstract: This study demonstrated that gel-like polyion complexes obtained by mixing of aqueous solution of chondroitin sulfate, heparin, and hyaluronic acid with that of chitosan were able to form their free-standing films using hot press treatments. These films, having thicknesses ca. 50 and 100μm, depending on the spacer thickness, were homogeneous and non-porous at the microscopic level, and were not water-soluble. The present fabrication process required neither cross-coupling agents nor introduction of other functional groups to the polysaccharides. Hydroxyapatite deposition on the film surfaces under body fluid conditions was also achieved. [Copyright &y& Elsevier]

Abstract: Polymeric micelles, as drug delivery vehicles, must achieve specific targeting and high stability in the body for efficient drug delivery. We recently reported the preparation of polyanion-coated biodegradable polymeric micelles by coating positively charged polymeric micelles consisting of poly(l-lysine)-block-poly(l-lactide) (PLys-b-PLLA) AB diblock copolymers with anionic hyaluronic acid (HA) by polyion complex (PIC) formation. The obtained HA-coated micelles showed significantly higher stability in aqueous solution. In this study, to evaluate the HA-coated polymeric micelles as a drug carrier, model drug release from the micelles and cytotoxicity of the micelles were investigated. The HA-coated micelles showed sustained release of model drugs and low cytotoxicity. It is known that there are receptors for HA on liver sinusoidal endothelial cells (LSEC). Specific interactions of HA-coated micelles with LSECs and Kupffer cells were investigated and compared with polymeric micelles coated with other polyanionic polysaccharides, i.e., heparin (Hep) and carboxymethyl-dextran (CMDex). Although Hep-coated micelles and CMDex-coated micelles were incorporated into both Kupffer cells and LSECs, HA-coated micelles were taken up only into LSECs. These results suggest HA-coated micelles have potential utility as drug delivery vehicles exhibiting specific accumulation into LSECs. [Copyright &y& Elsevier]

Abstract: Biocompatible polymer–magnetite hybrid nanoparticles were prepared by means of in situ synthesis of magnetite within polysaccharide hydrogel nanoparticles. Hydrogel nanoparticles were first fabricated by blending high-molecular-weight carboxymethyl cellulose as an anionic polymer, and low-molecular-weight chitosan as a cationic polymer to form polyion complexes (CC particles). These polyion complexes were then chemically crosslinked using genipin, a bio-based cross-linker, to form stable nanoparticles having a semi-IPN structure (CCG particles). Magnetite was lastly synthesized within CCG particles by the coprecipitation method to obtain polymer–magnetite hybrid nanoparticles (CCGM particles). The formations of CC, CCG and CCGM particles were mainly observed by transmittance, absorbance of genipin and TEM, respectively, and their hydrodynamic diameters and zeta-potentials were analyzed. It was confirmed that the hydrodynamic diameters and the zeta-potentials of these particles were significantly influenced by pH of the suspension, which was attributed to the charges of polymers. The diameters of CCGM particles were smaller than 200nm at any pH conditions, suggesting the possibility to apply them as drug delivery carriers. CCGM particles exhibited the responsiveness to a magnetic field in addition to their high dispersion stability, indicating their potential to be utilized as a biomaterial for hyperthermia. [Copyright &y& Elsevier]

Abstract: This review describes the design of polymeric micelles from block copolymers and their performances as nano-scale drug delivery systems, with emphasis on our recent work. The basic drug delivery system platform developed by our group consists of polymeric micelles comprising a core–shell structure with a versatile drug-loading hydrophobic core and biocompatible hydrophilic shell, and are several tens to one hundred nanometer in size. These characteristics are preferable to bypass both renal clearance and entrapment by the reticuloendothelial system, thus allowing subsequent accumulation within tumor tissues by the enhanced permeability and retention effect. Furthermore, polymeric micelles may be designed for enhanced biological performance by modification of the block copolymers to contain chemistries that can sense a specific biological environment. These “smart” micelles allow for target site-triggered drug release by reversible stabilization of the micelle structure and controlled intracellular trafficking (efficient endosomal release). Smart micelles designed with responsive features have demonstrated the utility in many cases compared to controls lacking such functionality. Additionally, the ability to control the size of polymeric micelles in the range of several tens to hundreds of nanometer significantly affects their longevity in the blood stream and efficiency of tumor tissue accumulation and penetration. In hypovascular tumor tissues, smaller polymeric micelles are more effective for tissue accumulation/penetration, bringing about stronger anti-tumor activity. All together, fine-tuning the structure of block copolymers enables preparation of polymeric micelles with versatile functions for treatment of many diseases including intractable cancer. [Copyright &y& Elsevier]

Abstract: The current study synthesized macromolecular magnetic resonance imaging (MRI) contrast agents constituted of the poly(ethylene glycol)-b-poly(l-lysine) block copolymer (PEG-P(Lys)). A chelate group, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), was attached to the primary amino group of the block copolymer in desired contents. Gd-DOTA-based macromolecular contrast agents were prepared from PEG-P(Lys) having DOTA (PEG-P(Lys-DOTA) and Gd(III) ions. All of the PEG-P(Lys) block copolymers having gadolinium ions (PEG-P(Lys-DOTA-Gd)) showed higher T 1 relaxivity (per gadolinium), r 1 =5.6–7.3mM−1 s−1, than that of a low-molecular-weight gadolinium-chelate, diethylenetriaminepentaacetic acid-gadolinium(III) (Gd-DTPA) at 9.4T. The study prepared the polyion complex (PIC) micelles from the amino groups of the lysine units and an oppositely charged polyanion, poly(methacrylic acid) or dextran sulfate, in an aqueous medium. In contrast, the fully DOTA-attached PEG-P(Lys-DOTA-Gd) formed a PIC with a polycation. Compared with partially DOTA-attached cationic PEG-P(Lys-DOTA-Gd), this PIC micelle yielded a forty percent decrease of r 1. This r 1 decrease was considered to result from a change in the accessibility of water molecules to gadolinium ions in the micelles'' inner core. The r 1 was decreased upon formation of the PIC micelle, and this change proved that our concept worked in vitro. Blood-circulation characteristics of PIC micelles were controlled by means of changing the molecular weight of the counter anion. The PIC micelles accumulated in tumor tissues, and MRI study showed T1W image of axial slice of tumor area was significantly enhanced at 24h after the injection. [Copyright &y& Elsevier]

Abstract: An siRNA-grafted polymer through disulfide linkage was prepared to improve the physicochemical properties and transfection efficacies of the polyion complexes (PICs) as a nanocarrier of siRNA. The siRNA-grafted polymer formed stable PICs due to its larger numbers and higher density of anionic charges compared with monomeric siRNA, leading to effective internalization by cultured cells. Following the endosomal escape of the PIC, the disulfide linkage of the siRNA-grafted polymer allowed efficient siRNA release from the PIC under intracellular reductive conditions. Consequently, the PIC from the siRNA-grafted polymer showed a potent gene silencing effect without cytotoxicity or immunogenicity, demonstrating a promising feature of the siRNA-grafted polymer to construct the PIC-based nanocarrier for in vivo siRNA delivery. [ABSTRACT FROM AUTHOR]

Abstract: For the development of an siRNA delivery system using polyion complexes (PICs) based on PEGylated nanogel consisting of a cross-linked poly[2-(N,N-diethylaminoethyl) methacrylate] (PEAMA) gel core and tethered poly(ethylene glycol) (PEG) chains, quaternary ammonium groups were introduced in the polyamine gel core to enhance the binding ability with siRNA and the stability of the PICs. Consequently, the quaternization of the polyamine core of the nanogel facilitated the binding ability with siRNA at a low N/P ratio, and the stability against polyanion displacement was enhanced as the degree of quaternization (DQ) of the nanogel increased. Although the installation of the positively charged quaternary ammonium moieties in the core of the nanogel resulted in the increment of the ξ-potential of the PICs (e.g. +23mV for DQ=100%), the cytotoxicity was reduced with the increase of DQ presumably due to the hydrophilic character of the quaternary ammonium groups. The installation of quaternary ammonium groups in the core of the nanogel enhanced the endogenous gene silencing activity against the survivin gene in human hepatocarcinoma (HuH-7 cells), especially, the partly quaternized polyamine nanogel (DQ=10%) showed the highest gene silencing ability among the quaternized polyamine nanogels, including the tertiary amine nanogel. The cellular uptake analysis of the Rhodamine B-labeled Q-nanogel/fluorescein-labeled siRNA complex revealed that the quaternization of PEAMA moieties enhanced the cellular uptake level of fluorescein-labeled siRNA with the increase in DQ, whereas the cellular uptake of the Rhodamine B-labeled Q-nanogels was almost of the same level regardless of the DQ value, indicating that significant cellular uptake of the fluorescein-labeled siRNA is most likely due to the enhancement of the binding ability with siRNA in the serum-containing medium. Note that the endosomal escape efficiency was reduced with increase in the DQ value due to the decrease in the buffering capacity (tertiary amino groups) of the PEAMA core. On the basis of these results, the ratio of quaternary ammonium groups to tertiary amino groups in the core of the nanogel plays a pivotal role in the achievement of significant gene silencing through enhanced cellular uptake (quaternary ammonium groups) and subsequent endosomal escape (tertiary amino groups). [Copyright &y& Elsevier]

Abstract: Palladium nanoparticles stabilized by a polyion complex composed of poly{4-chloromethylstyrene-co-(4-vinylbenzyl) tributylammonium chloride} and poly(acrylic acid) were easily recovered by filtration after pH treatment. The polyion complex stabilized palladium nanoparticles have high catalytic activity for the Suzuki and Heck reactions in water. [ABSTRACT FROM AUTHOR]

This research focuses on the preparation of polyion complex having spironaphthoxazine and their photochromic behaviors including absorbance and fluorescence switching. The polyion complex was prepared by the ion complex formation between spironaphthoxazine 3 (cationic monomer) and poly(styrene-sulfonic acid) (anionic polymer). Spironaphthoxazine group showed reversible photoisomerization in this polyion complex upon UV irradiation. It reversibly changed the fluorescent intensity by alternative irradiation with ultraviolet and visible light. The photoinduced ionic conductivity in polyion complex solution gradually increased upon UV irradiation and subsequently decreased in the dark. [ABSTRACT FROM AUTHOR]

Abstract: We describe the preparation and characterisation of inorganic–organic hybrid block copolymer silver nanoparticles via the preparation of spherical multi-responsive polymeric micelles of poly(N-methyl-2-vinyl pyridinium iodide)-block-poly(ethylene oxide), P2MVP38-b-PEO211 and poly(acrylic acid)-block-poly(isopropyl acrylamide), PAA55-b-PNIPAAm88 in the presence of AgNO3. Hence, the P2MVP and PAA segments were employed to fix Ag+ ions within the micellar core (25°C) or shell (60°C), while the PEO segments ensured spontaneous reduction of Ag+ ions into metallic Ag, as well as colloidal stabilisation. Spherical and elongated composite core–shell(–corona) nanoparticles (CNPs) were formed containing several small, spherical silver nanoparticles within the micellar core or shell. As the co-assembly of the oppositely charged copolymers into micelles is electrostatically driven, the CNPs can be destabilised by, for example, addition of simple salts, i.e., the CNPs are stimuli responsive. CNP size and morphology control can be achieved via the preparation protocol. For example, heating to 60°C, i.e., above the PNIPAAm LCST, results in core–shell–corona CNPs with the Ag-NPs situated in the aggregate shell. [Copyright &y& Elsevier]

Abstract: We have developed a rapid and simple gas toxicity evaluation system based on bioluminescence inhibition of a marine-derived wild luminous bacterium, Vibrio fischeri. The luminous bacteria were trapped using a thin polyion complex membrane in order to allow semi direct contact between the bacteria and toxic gases. Bioluminescence inhibition ratios of the present system to six reference gases, including benzene, trichloroethylene, acetone, NO2, SO2, and CO, were evaluated, and dose–response relationships were successfully obtained after 15min of gas exposure, except for CO gas. The sensitivity to the five gases except for CO gas of the present system was 1–3 orders of magnitude higher than that in acute animal tests. The present system also allowed for the evaluation of overall toxicity of some environmental gases containing various chemicals. These results clearly demonstrated that the present system would be a valuable prototype for rapid and on-site acute toxicity detection of a gas mixture, such as environmental gases. [Copyright &y& Elsevier]

Abstract: Poly(vinylamine), the simplest polycation with primary amines, was applied to interpenetrating polymer networks (IPN) with poly(acrylic acid). N-Vinylformamide (NVF) was employed for amino-protected monomers to control electrostatic balance. pH-responsivities of IPNs varied, depending on the hydrolysis conditions and acrylic acid (AAc) concentration of the second network. Poly(N-vinylacetamide)-co-poly(N-vinylformamide) (4/6, mol/mol) was employed for the first network, subsequently hydrolyzed with 50% amide groups, and the second network was polymerized with 0.25molL−1 AAc, extremely shrunken hydrogels with polyion complex were formed at pH 7, showing that the controlled amount of highly active primary amines are available in IPN. [Copyright &y& Elsevier]