Glycopolymer Nanobiotechnology.

Review pubs.acs.org/CR

Glycopolymer Nanobiotechnology Yoshiko Miura,* Yu Hoshino, and Hirokazu Seto Department of Chemical Engineering, Graduate School of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395, Japan systems. To accumulate these weak interactions, the biological ligands are usually able to bind in a multivalent way. In particular, it is well-known that saccharide interactions are greatly affected by the multivalent effect.4 Though saccharide− protein interactions with monomeric sugars are weak, with a dissociation constant (Kd) in the order of millimolar, interactions that involve multivalent binding are much stronger with Kd values on the order of micromolar.5,6 For glycolipids, Kd values for the saccharide−protein interactions become smaller with increasing glycolipid ratios, which suggests the contribution of a multivalent effect.7 Dense microdomains of CONTENTS lipids or “rafts” mediates multivalent saccharide−protein 1. Introduction to Glycopolymers 1673 interactions.8 These lipid raft structures are important in 2. Structure and Function of Glycopolymers 1674 various saccharide-mediated cellular interactions.4 The den2.1. Early Work on Glycopolymers 1674 dritic saccharide structure of glycoproteins enables a strong 2.2. Structure of Glycopolymers and the Multiinteraction with lectins via multivalency. Polysaccharides, such valent Effect 1674 as glycan and glycosaminoglycans, also present saccharides in a 2.3. Controlled Polymerization of Glycopolymers 1676 multivalent way. The natural saccharides have multivalent 2.4. Branched Glycopolymers and Glycodenstructures that enable multivalent binding and, hence, strong drimers 1677 interactions.9 2.5. Physical Properties of Glycopolymers 1677 Saccharide−protein interactions are found throughout living 3. Polymer Nanomedicine using Glycopolymers 1678 systems. Cell surfaces are covered by various saccharides. 3.1. Nanomedicine Using Glycopolymer MultiSaccharide interactions are involved in various biological events, valency 1678 including cell−cell adhesion, cell recognition, and cell differ3.2. Glycopolymers that Control Cell Functions 1680 entiation.4 In addition, pathogens, such as viruses and toxin 3.3. Glycopolymers for Biosensing 1680 proteins, infect cells though saccharide−protein interactions. 3.4. Glycopolymers for Drug Delivery and Gene Notable examples are the interactions between influenza viruses Delivery 1681 and sialyl oligosaccharides, the HIV and HIV receptors, cholera 3.5. Glycopolymer Conjugation to Biomacromotoxins and glycolipids, and Shiga toxins and glycolipids. lecules 1683 4. Conclusion and Outlook 1683 Saccharide interactions are also involved in the folding, Author Information 1684 transportation, and quality control of proteins (Table 1). Corresponding Author 1684 Saccharide recognition proteins, known as lectins, usually Notes 1684 have multimeric structures. The lectins from both plant and Biographies 1684 mammalian cells have been studied.10−12 The plant lectin Acknowledgments 1684 concanavalin A (ConA) has been studied thoroughly since the Abbreviations 1684 1970s.10 The detailed ConA structure was first analyzed by XReferences 1685 ray crystallography,13−19 and this triggered the intense investigation of saccharide−protein interactions.20−24 Studies on ConA have provided extensive information on saccharide− protein interactions. ConA has a homo tetramer structure with 1. INTRODUCTION TO GLYCOPOLYMERS four sugar binding sites. Previous studies have revealed that the Molecular recognition plays an important role in living density of mannose (Man) residues and cross-linking via systems.1,2 Representative molecular recognitions in living multiple binding play important roles in the amplification of organisms are saccharide−protein, protein−protein, and saccharide−protein interactions. antigen−antibody interactions. These biological interactions are possible through molecular interactions, including hydroSpecial Issue: Frontiers in Macromolecular and Supramolecular phobic and electrostatic interactions and hydrogen bonding.3 Science Though each individual molecular interaction is weak, the accumulation of several interactions makes the overall effect Received: April 27, 2015 strong, which results in the ability to control complex biological Published: October 28, 2015 © 2015 American Chemical Society

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DOI: 10.1021/acs.chemrev.5b00247 Chem. Rev. 2016, 116, 1673−1692

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Table 1. Examples of Saccharide Recognition by Proteins, Cells, and Pathogens lectin

cell pathogen

target

saccharides

concanavalin A (ConA) Ricinus communis agglutinin(RCA)120, RCA60 peanut agglutinin Sambucus nigra lectin selectins (E-, L-, P-) galectins (−1 ∼ −15) hepatocyte, HepG2 macrophage Shiga toxins (E. coli O-157, H-7, etc.) Vibrio cholera toxin hemagglutinin from influenza virus type A for human hemagglutinin from influenza virus type A for avian E. coli type 1 E. coli P-adhesin HIV-gp120−DC-SIGN

α-Man/α-Glc β-Gal/β-GalNac β-Gal Neu5Ac(α2−6)Gal/GalNAc Sialyl LewisX, Sialyl LewisA β-Gal β-Gal, Gal(β1−4)GlcNAc Man Gb3: Gal(α1−4) Gal(β1−4)GlcCer GM1: Gal(β1−3) GalNAc(β1−4) (Neu5Acα3) Gal(β1−4) GlcCer Neu5Ac(α2−6)Gal Neu5Ac(α2−3)Gal α-Man Gal(α1−4)Galβ Man

1990s.42−47 In early work, the glycopolymers were mainly synthesized by radical polymerization, because the radical reaction is orthogonal to the hydroxyl group on the saccharide side chain. Other glycopolymers have been prepared by a polymer reaction using polymers with functional groups, such as poly(L-glutamic acid),48−51 alginic acid,52,53 and poly(Nacryloxysuccinimide).42 The polymers prepared by free radical polymerization show polydispersity but exhibit large enough multivalent effects to function as biomaterials. The Akaike and Kobayashi groups have cultured hepatocytes with lactose substituted polystyrene poly(N-p-vinylbenzyl-Dlactonamide) (PVLA) in vitro.54−61 Hepatocytes are known to have an affinity for β-Gal and LacNAc (Gal(β1−4)GlcNAc) through the ASGP-R, and Gal is considered one of the key factors in the culture of hepatocytes. However, as we described above, saccharide−protein interactions are generally weak, and it has been difficult to use saccharides for cell-culture materials. The strong interactions of glycopolymers have enabled specific cell cultures via the Gal-ASGP-R specific interaction. The Akaike group has also reported hepatocyte specific drug delivery with PVLA in vivo and in vitro.62−64 This group showed that the saccharide structure and density induces a specific response to hepatocytes, which revealed the curious aspect of saccharide−protein interactions.65−67 The function of the saccharides on lectins had been unclear until the 1990s, because it was unknown what role the weak interactions could play. However, knowledge of the effect of multivalency and the use of synthetic glycopolymers has played an important part in clarifying the function of the saccharides. The Whitesides group designed glycopolymers with sialic acid groups that inhibited the hemagglutinin of influenza viruses in vitro.42−47 These glycopolymers inhibited the aggregation of erythrocytes. Glycopolymers were prepared with various sugar densities, and the polymers showed a much stronger inhibitory effect than monomeric sialic acid. The glycopolymers with more modest sugar densities showed the strongest inhibitory effect, and the polymer structure also affected the inhibition. The universality of the polyvalent interaction has been demonstrated using other polyvalent ligands, including the interactions between a polyvalent peptide and a toxin68 and polyvalent vancomycin and bacteria.69

To date, mammalian lectins have not been studied as thoroughly as plant lectins. Molecular recognition using mammalian lectins was first investigated in studies of the galectins.25−28 Galectins have a specific multimeric structure, which recognizes galactose (Gal) and controls the cell functions of apoptosis, adhesion, and migration. In addition, the functions of a mammalian lectin, the asialoglycoprotein receptor (ASGPR), in hepatocytes have been studied in detail.29,30 It has been reported that the ASGP-R interacts with a Gal cluster and is involved in the clearance of red blood cells. The saccharide interaction with the ASGP-R can be applied to hepatocyte cultures to mediate cell adhesion. Previous studies have clearly shown the importance of the multivalent effect in saccharide−protein interactions. To investigate the multivalent effect, the use of multivalent compounds or “glycoclusters” is indispensable, and many groups have reported syntheses of glycocluster compounds. Examples of glycoclusters include liposomes with glycolipids,31 glycocalixarenes,32 glycocyclodextrins,33 glycopeptides,34 and glycopolymers. Among the various synthetic glycoclusters, glycopolymers have been the subject of much attention (Figure 1).35−40 In this review, we define glycopolymers as polymers

Figure 1. Schematic structures of glycopolymers with linear, dendrimer, and star polymer structures.

carrying pendant saccharides. Since glycopolymers have larger valencies than other multivalent compounds, they show the largest amplification effects in molecular recognition. Glycopolymers are able to be prepared as nanomaterials by controlled polymerization. In this section of the review, we discuss glycopolymers and their application for biotechnology.

2. STRUCTURE AND FUNCTION OF GLYCOPOLYMERS 2.1. Early Work on Glycopolymers

2.2. Structure of Glycopolymers and the Multivalent Effect

A glycopolymer carrying lactose was first synthesized in the 1980s by the Kobayashi group,41 and the Whitesides group investigated glycopolymers and multivalent interactions in the

Early studies demonstrated the multivalent effect of saccharides and its practical usefulness. The use of glycopolymers 1674


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Figure 2. Illustration of the concept of the multivalent effect of glycopolymers: (a) comparison of monovalent and multivalent binding, including the definition of cooperativity; (b) multivalent binding of glycopolymers with different DP to tetrameric lectin; and (c) the multiple binding mode of a polyvalent saccharide to a lectin.

Figure 3. Representative monomer structures for the synthesis of glycopolymers for (a) radical polymerization, including living radical polymerization, (b) ring-opening metathesis polymerization, and (c) polymerization with subsequent saccharide addition.

polymerization (DPs) (based on molecular weight). The Kiessling group studied the affinity to ConA of glycopolymers carrying Man with different DPs, and the polymers with higher DPs showed larger binding affinities.70 The Miura group have studied the binding constants of lactose glycopolymers with different DPs to RCA120.71 Glycopolymers with a high DP

contributes to both enthalpy gain and cooperativity increases on binding. Glycopolymers have polyvalent saccharides and show amplification effects (Figure 2).35−40 The multiple binding of glycopolymers can result in a gain in the binding enthalpy. The multiple binding of a polymer to a lectin has been studied using glycopolymers with different degrees of 1675


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(RAFT) polymerization,91 and single-electron transfer living radical polymerization (SET-LRP)93 have been successfully applied in the synthesis of glycopolymers. In spite of the bulky structure of the monomers, saccharide derivatives of styrene, methacrylate, and acrylate have been polymerized by living radical polymerization. The first reported living radical polymerization of a glycopolymer was performed by Ohno et al.94 PVLA was polymerized via nitroxide-mediated living radical polymerization using di-tert-butyl nitroxide in DMF, with an acetylated monomer (AcVLA). Other groups have also reported the polymerization of glycopolymers with styrene by nitroxide-mediated living radical polymerization.95−101 Chen et al. reported the synthesis of various poly(styryl sugar)s using 2,2,6,6,-tetramethylpiperidine-1-oxyl (TEMPO).97,98 Kakuchi et al. reported the living radical polymerization of glycopolymers with polystyrene, preparing homopolymer, block copolymer, and star polymers with TEMPO.99−101 ATRP is a representative method of living radical polymerization. Ohno et al. also first reported the ATRP of a glycopolymer using a glucose (Glc) methacrylate derivative (3-O-methacryloxyl-1,2,5,6-di-O-isoproylidine-D-glucoside).102 They reported the preparation of the glycopolymer and block copolymer in high yield. Narain and Armes synthesized glycopolymers, using CuBr with a macroinitiator, containing poly(ethylene oxide) (PEO), poly(propylene oxide), and poly(ε-caprolactone).103−105 The conversion was dependent on the solvent system and the macroinitiator, and they were able to polymerize glycopolymers of 2-lactobionamidoethyl methacrylate (LAMA) and 2-gluconamidoethyl methacrylate (GAMA) in aqueous solutions without any protection of the hydroxyl groups. The advantage of ATRP is the versatility, with the choice of different initiators enabling the synthesis of various types of polymers and use of different solvents. The Maynard group reported the glycopolymers with a functional initiator such as a biotin and pyridyl group.36 Much attention has also been paid to the use of surfaceinitiated ATRP (SI-ATRP) to fabricate biointerfaces. SI-ATRP can be used to produce glyco-polymer brushes, which are useful biointerfaces for glyco-chips and cell cultivation.106−109 The densities of the polymer brushes are able to be controlled by the amount of immobilized initiator.106,107 Recently, a novel method of ATRP, SET-LRP, has been developed by the Percec group.110−112 Living radical polymerization using SET-LRP enables a high yield and fast polymerization. The Haddleton group has reported the controlled polymerization of various polymers using SET-LRP, including glycopolymers.113−115 The Haddleton group is investigating glycopolymers synthesized with precise sequence control of the block-glycopolymers, which is an important concept for polymer nanomedicine. RAFT is another important method of living radical polymerization, which is performed with thiocarbonyl additives.91 RAFT polymerization is suitable to the polymerization of bulky monomers, and there have been various report of polymerization of glycopolymers. McCormick et al. first synthesized a glycopolymer of 2-methacryloxyethyl glucoside with a RAFT reagent.116 The Stenzel group reported living radical polymerization of various glycopolymers with the RAFT method. Glycopolymers have been prepared using polyacrylamide,117−122 polymethacrylate,123−126 polyvinylester,127 polyacrylate,128 and polyvinyl triazole129 with Glc, Man, and Nacetylglucosamine (GlcNAc), resulting in a variety of glycopolymer structures, including simple linear structures,

showed larger binding constants than those with a low DP because of the multiple binding to one lectin (Figure 2b). Glycopolymers with a high DP can cross-link lectin and showed a larger binding affinity because of the enthalpy gain with multiple binding. Another important attribute of glycopolymers is the ability to present multiple binding modes to lectins and cells (Figure 2c). Glycopolymers with a shorter DP show larger affinities than monomeric saccharides, even though the polymers only bind to one sugar recognition site. The polyvalent ligand can provide various binding modes compared with monovalent ligands, which is favorable in terms of entropy. The cooperativity entropy effect is affected, not only by the multiple binding mode but also by the ligand spacer, molecular dynamics,72 and polymer backbone flexibility.1,2 Frequently, flexible linkers are connected to the saccharide to increase the affinity.70 Use of a hydrophobic linker, such as benzene, has been reported to increase the binding affinity because of the hydrophobicity.44 In glycopolymers with phenyl isocyanide, the glycopolymers showed low cooperativity because of the rigid polymer structure.73 The Whitesides group defined the concept of the cooperativity of multiple binding as shown in Figure 2a. The Kiessling group investigated the affinity of various glycopolymers70 and highlighted the complexity of multivalent effects. The binding amplification effect of a glycopolymer is not in simple proportion to the number of saccharides and saccharide recognition units. Generally, the observed Gibbs energy change values are smaller than those obtained from a simple calculation based on the saccharide number (Figure 2a). In glycopolymers, the sugar binding efficiencies are not high because of the limited number of sugar binding sites and the sugar motility, which are possible disadvantages in the use of glycopolymers as polyvalent ligands. Despite these known weak points, most of the glycopolymers studied have been reported to amplify saccharide−protein interactions.6,35−40 Though the basic mechanism of the multivalent effect is the same for all of the lectins, the distance between the saccharide recognition sites is unique for each protein. While the distance between the saccharide recognition sites of ConA is 6.5 nm,13−16,74 those of the AB5 toxins in B subunits,75 such as in Shiga toxins76−78 and the cholera toxin79−81 are much shorter ca. 1−3 nm. The number of sugar recognition sites is more than 5 in AB5 toxins. Therefore, glycopolymers easily provide for several binding sites with AB5 toxins, which results in stronger binding.82−85 Similarly, the hemagglutinin of influenza viruses has densely packed trisaccharide recognition sites.86−88 Many lectins exist on cell membranes. The addition of glycopolymers to the cell induces cross-linking and selfassembly of lectins. The assembly of lectins makes a great contribution in terms of a multivalent effect to the control of cell functions and signal transduction.1,54 2.3. Controlled Polymerization of Glycopolymers

Controlled polymerizations have been reported using various methods;89−93 these methods have also been applied to the preparation of glycopolymers. The examples of monomer structures for controlled polymerization reactions are listed in Figure 3. Even though the monomers possess a bulky side chain that causes steric hindrance, recent advances in polymer chemistry have enabled living polymerization. Various living radical polymerization techniques, including nitroxide-mediated polymerization, 92 atom-transfer radical polymerization (ATRP),89,90 reversible addition-fragment chain transfer 1676


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block polymers125 star polymers,126 nanoparticles,129−131 and graft-polymers.119 More diverse monomers can be used with RAFT than with ATPR and nitroxide-mediated living radical polymerization. Another advantage of RAFT polymerization is the facile modification of the polymer terminal. The polymer terminal thiocarbonyl group of the RAFT reagent is easily converted to thiol, which is available for many useful modifications, including Au−S bond formation, Michael addition with maleimide, the thiol−ene reaction, and disulfide bond formation.132 These modification methods provide for versatile hybrid materials with glycopolymers (Figure 4).

Synthetic nanoparticles of branched glycopolymers are one of the interesting types of polymer for biological applications. Glycodendrimers have been intensively studied as models of glycoproteins. One of the features of dendrimers is a uniform molecular structure and a molecular weight similar to proteins. Aoi et al. first reported the synthesis of glycodendrimers by the modification of polyamidoamine (PAMAM) dendrimers.153 The Roy group has reported the synthesis of various types of glycodendrimers.154 For example, this group has prepared dendritic sialosides with PAMAM dendrimer backbones and investigated the affinity of these dendrimers to a sialic acidrecognizing lectin. The affinity was analyzed by the inhibition of glycopolymer−lectin binding, which was ca. 100 times higher than with the monomeric saccharide in view of IC50.155,156 Since PAMAM dendrimers are commercially available, the synthesis of various glycodendrimers based on this scaffold have been reported. Wolfenden et al. reported the syntheses of αMan modified glycodendrimers from the isothiocyanate reaction with amines and found the affinity of the glycodendrimers to ConA was related to the multivalency of the generated glycodendrimers.157 Modified PAMAM dendrimers, as well as other dendrimers, have been investigated for use in nanomedicine. The various attributes of glycodendrimers, such as size, sugar multivalency, electrostatic properties, self-assembling properties, and protein resistance, have an effect on biological funcions.157,158 These properties of glycodendrimers are a function of the structure of the dendrons. Glycodendrimers with poly(propyleneimine) have been investigated as drug carriers.159,160 The Percec group has reported the synthesis of Janus glycodendrimers and analyzed the resulting selfassembling structures to provide information on specific molecular recognition.161−163 Similar to the preparation of glycopolymers, click reactions have been investigated for glycodendrimer synthesis, which enables facile and precise syntheses without the use of protecting groups.164,165 Hyperbranched and star polymers can also provide spherical multivalent structures. The synthetic techniques to prepare these polymers are based on the synthesis of the linear glycopolymers as discussed in section 2.3. The Stenzel group has reported the synthesis of star glycopolymers.128 The Müller group has reported hyperbranched glycopolymers prepared via ATRP, including nanoparticle and nanocarbon hybrid-glycopolymers.166,167 The Perrier group reported the hyper branched glycopolymers by RAFT living radical polymerization.168 The hyperbranched polymers were easily synthesized by living radical polymerization, using the addition of a branching reagent. Hyperbranched polymers spontaneously form nanoparticles, which are useful in nanomedicine and as drug carriers. The application of these branched polymers to nanomedicine will be described in section 3.

Figure 4. Terminal functionalization of glycopolymer via RAFT living radical polymerization.

Recently, the use of a two-step reaction has been reported, which enables facile and precise glycopolymer preparation. Since the bulky side group of a saccharide hinders the polymerization reaction, it is difficult to use living radical polymerization of saccharide derivatives to provide polymers with a particular design. Hence, monomers with small reactive functional groups are polymerized using living radical polymerization, and the subsequent polymers are then modified by further chemical reactions.133−136 The Haddleton group has reported the living radical polymerization of acetylenesubstituted methacrylate, to which azide-terminated saccharides were added by click chemistry.137−139 The Bertozzi group prepared and polymerized a methyl vinyl ketone, and prepared a glycopolymer by an addition reaction with aminooxyterminated saccharides.140−142 Furukawa et al. reported glycopolymer preparation by the addition reaction of sugars to an aminooxy side chain,143 which is the reverse of the Bertozzi method. Boyer et al. prepared glycopolymers via living radical polymerization of an activated ester [3-(benzylsulfanylthiocarbonylsulfanyl)-propionic acid] and amide formation with an amine-terminated saccharide.144 You et al. also reported glycopolymer synthesis using a thiol−ene reaction.145,146 The combination of living radical polymerization and the addition of saccharides via an orthogonal reaction is a facile method to prepare glycopolymers with well-defined structures. Ring-opening metathesis polymerization (ROMP) is another important method to fabricate well-defined glycopolymers because it is tolerant of bulky side-chains and harsh solvents. The Kiessling group has reported the preparation of glycopolymers via ROMP.147−151 This group prepared various glycopolymers with different molecular weights and densities, which were investigated in terms of the molecular recognition of proteins, cells, and bacteria, including details of the molecular recognition and the control of cell functions. Saccharide addition to polymers via ROMP with succinimide norbornene has also been reported in the synthesis of well-defined glycopolymers.152

2.5. Physical Properties of Glycopolymers

Since glycopolymers have hydrophilicity from the saccharides and hydrophobicity from the polymer backbone, the polymers are amphiphilic. This amphiphilicity induces the self-assembly of glycopolymers in aqueous solutions. Polystyrene-substituted glycopolymers form helical rodlike structures because of the amphiphilicity and chiral properties of the glycopolymers. Wataoka et al. have reported rodlike structures formed by maltopentaose and lactose carrying polystyrene polymers using small-angle X-ray scattering analysis.169−171 Polystyrene carrying lactose (PVLA) glycopol-

2.4. Branched Glycopolymers and Glycodendrimers

Spherical polymer structures of glycopolymers are important for the use of polymers in medicine and drug delivery. 1677


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Figure 5. Self-assembling structures of glycopolymers. (a) Block glycopolymers formed various kinds of self-assembling structures based on the molecular packing parameters and (b) block glycopolymers with amphiphilicity formed nanoparticles.

methacrylate. The resulting self-assembling structures formed nanospheres, wormlike micelles, and vesicles, and have potential applications as drug carriers. The formation of the structures was controlled by the monomer ratio and degree of polymerization. The Stenzel group has reported the synthesis of various block-glycopolymers, including stimuli-responsive glycopolymer micelles.180,181 Other groups have also reported the formation of polymer micelles of block glycopolymers, based on the amphiphilicity and self-assembling properties (Figure 5b).104−108,145,146 Although uniform self-assembled structures of glycopolymers have been seldom reported, many groups have reported the formation of nanoparticles. Dendrimers are also useful as a component of supramolecules. The Percec group has investigated self-assembling dendrimers under various conditions.182 This group has reported the preparation of Janus type glycodendrimers, which formed vesicles in aqueous solution.161−163 The vesicles (glycodendrimersomes) are molecular assemblies with diameters of several hundred nanometers, which were observed to regulate biological signaling with galectins. The molecular interactions could be controlled by altering the structure of the glycodendrimersomes.

ymers formed isotactic structures and showed strong circular dichroism based on the amphiphilicity and chirality of the polymers.172 PVLA polymers formed helical rodlike structures with a hydrophobic cavity. The Miura group reported the nanowire formation with the self-assembling ability of PVLA glycopolymers for nanowire formation.173 The hydrophobic cavity of the glycopolymer incorporated π-conjugated polymers of polythiophene to form the polymer nanowire, which is similar to the complex formation of natural polysaccharides.174 Though glycopolymers with polystyrene form rodlike structure in aqueous solution, the glycopolymers can be adsorbed onto hydrophobic substrates. Akaike et al. reported the coating of PVLA polymers onto hydrophobic polystyrene, which was used to prepare hepatocyte cultures.55 The Miura group investigated the polymer adsorption on the hydrophobic interface.175,176 A glass substrate was made hydrophobic using a silane coupling reagent, and the hydrophobic−hydrophilic micropattern was prepared by photolithography. The glycopolymers adsorbed only on the hydrophobic part. The saccharide micropattern was easily prepared by the simple immersion of the patterned substrate in the glycopolymer solution. The glycopolymer micropattern was applied to the cell cultivation of two kinds of cells. Block copolymers of glycopolymers with hydrophobic polymers have been used for the preparation of polymer micelles.125 It is well-known that lipids form various supramolecules, including micelles, rodlike micelles, vesicles, and hexagonal reverse micelles.177 The Armes group has reported various self-assembled block glycopolymers (Figure 5a).178 The self-assembling structure of lipids is determined by the packing paramters.179 The Armes group synthesized well-defined amphiphilic glycopolymers and investigated in detail the lipidlike self-assembling properties of the glycopolymers, using block polymers with galactose methacrylate and hydrophobic

3. POLYMER NANOMEDICINE USING GLYCOPOLYMERS 3.1. Nanomedicine Using Glycopolymer Multivalency

As mentioned in the Introduction to section 2.2, the multivalency of glycopolymers amplifies the molecular interactions with lectins, bacteria, viruses, and cells. Glycopolymers strongly interact with pathogens and are useful in polymer medicines. In some cases, the affinities of glycopolymers are comparable to those of antibodies and antigens. 1678


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Figure 6. Concepts of glycopolymer nanomedicines and applications.

The inhibitory effect of amyloid β aggregation was dependent on the saccharide density and the molecular weight of the glycopolymer. The inhibition of viruses by glycopolymers has been reported. As mentioned in section 1, the saccharide−protein interaction is related to the infection of viruses.4 The influenza viruses infect cells by the binding of hemagglutinin and neuraminidase to sialyl oligosaccharides on the cell surface. The Whitesides43−47 and Kobayashi48,196−198 groups have reported glycopolymers that interact with influenza viruses. Strong interactions between the hemagglutinin molecules of various types (A, B, C, and avian) of influenza viruses and glycopolymers having polyacrlyamide,43 polystyrene,196 and poly(glutamate)197 backbones have been reported. The Roy group has synthesized glycodendrimers and glycopolymers with sialic acid that bound to the hemagglutinin moieties of various types of influenza viruses,199 where the strongest inhibitory effect was more than 1000 times higher than with the monomeric sialic acid. The glycodendrimer efficiently inhibited infection of the influenza virus in mammalian cells. Another example of saccharide-mediated viral infection is the HIV. Multivalent α-Man on the envelope glycoprotein of the HIV interacts with dendritic cell-specific ICAM-grabbing nonintegrin (DC-SIGN). Becer et al. reported that a glycopolymer carrying α-Man was able to interact with DC-SIGN.200−203 Glycopolymers carrying Man were synthesized by living radical polymerization and click chemistry, and the resulting polymer inhibited the binding of DC-SIGN to gp120. The greatest inhibitory effect was exhibited by the glycopolymer with the highest Man density. Saccharides are able to influence the inflammatory response through binding to selectins. Glycopolymers have been used as selectin inhibitors. Selectins are classified as L-, P-, and Eselectins.4 Miyauchi et al. prepared polyacrylamide polymers carrying sialyl Lewis X, which interacted with E-selectins and inhibited the cell adhesion of HL-60.204,205 Sasaki et al. synthesized polyacrylamide derivatives carrying sialyl Lewis X mimics that bound to L-selectin.206,207 The Chaikof group reported PEO dendrimer-like glycopolymers, which interacted with L-selectin to inhibit U937 cell adhesion.208 The Kiessling group has synthesized glycopolymers with sulfated groups, and the sulfo-Lewis X moieties were shown to interact with selectins.209 Oligosaccharides are needed for the synthesis of glycopolymers that may be useful in medicine. However, the syntheses of oligosaccharides are usually tedious and proceed in low yield. To overcome these synthetic difficulties, multivalent oligosaccharide mimics have been investigated. Sasaki et al. have developed the glycomodule method, where a few different types of saccharides are displayed along one polymer to mimic

Saccharide interactions have already been used in medicines, including in the influenza virus inhibitors, oseltamivir and zanamivir,183 where interactions, such as hydrophobicity and charge, are induced to amplify the affinity. The overall interaction of a glycopolymer with a target is the accumulation of several weak interactions, which is similar to antibody binding. The strong interaction between glycopolymers and target pathogens may be useful in the development of novel polymer-based therapeutics (Figure 6). The molecular recognition of glycopolymers with lectins has been reported by many groups. Interestingly, many lectins are toxic and often pathogenic but are able to be inhibited by glycopolymers, glycodendrimers, glycopolymer micelles, and glycopolymer brushes. For example, β-Gal or lactosesubstituted polymers are able to bind to the deadly biological toxin ricin.184 The Stenzel group has reported a glycopolymer that was able to bind to ricin, where the density and linker structure of the glycopolymer was critical to the ricin binding. Nagatsuka et al. prepared a glycopolymer-conjugate carrying lactose with magnetic nanoparticles and gold nanoparticles, which bound to ricin.185−187 The glycopolymer captured ricin for detection and removed ricin from a solution. AB5 toxins are also toxic and pathogenic. Glycopolymers carrying saccharide ligands efficiently inhibit AB5 toxic proteins, such as Shiga toxins and the cholera toxin.188 Dohi et al. synthesized a glycopolymer carrying a trisaccharide segment of Gb3, which effectively neutralized Shiga toxin-1 and E. coli O157 by multivalent effect.84 Gargano also reported that a glycopolymer with a trisaccharide was able to inhibit Shiga toxin.83 Glycodendrimers with Gb3 trisaccharides have also been reported to inhibit Shiga toxins.189 The inhibition of the Shiga toxins was dependent on the distance between sugars and the linker structure of the glycopolymers. Shiga toxin-1 showed a strong interaction with glycopolymers, independent of the linker structure, but the affinity of the glycopolymers to Shiga toxin-2 was strongly dependent on the linker structure. Glycopolymers carrying Gal have been shown to inhibit cholera toxin,190−192 though the natural ligand is not Gal but GM1. The Kiick group has investigated the cholera toxin inhibition in detail and found that appropriate sugar density (ca. 3.5 nm) is important for strong binding. Richards et al. also found that the interaction between a glycopolymer and the cholera toxin is strongly related to the linker structure of the glycopolymer.193 Inhibition of the cholera toxin was also found to be dependent on the density of the sugar groups. Another toxic protein, the Alzheimer’s amyloid β protein, has been observed to be neutralized by glycopolymers. We have synthesized glycopolymers carrying 6-sulfo-β-D-GlcNAc.194,195 This sulfonated glycopolymer mimics glycosaminoglycan, and inhibited the aggregation of amyloid β, neutralizing the toxicity. 1679


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oligosaccharide functions.206 Jones et al. have synthesized a glycopolymer with secondary binding motifs that mimics the branched structure of oligosaccharides.210 Most of the studies of polymer medicine were carried out in vitro. Since the glycopolymers have strong activities to the target due to the multivalent effect, glycopolymers have a great potential in vivo for series of novel medicines though they needs clinical experiment. 3.2. Glycopolymers that Control Cell Functions

Figure 8. Glycopolymers with lipid terminals were displayed on the cell surfaces, and saccharide−cell functions were analyzed. The inset shows the representative structure of glycopolymers for glycocalyx engineering. The polymers were synthesized by RAFT living radical polymerization of polyMVK with saccharide addition. Various saccharides with aminooxy groups were conjugated with the polymers.

Most saccharides are present on the cell surface to enable interaction with other cells. Therefore, glycopolymers can be used in cell cultivation and as scaffolds for tissue engineering. In particular, glycopolymers have been investigated for use in hepatocyte cultivation.55,56 The interaction of glycopolymers with hepatocytes induces a round shape because of a strong interaction with the ASGP-R. The Kiessling group has reported precise control of the synthesis of glycopolymers using ROMP,71,150−152 to analyze molecular recognition with lectins and cells. Glycopolymers carrying β-Gal, with different degrees of polymerization, were synthesized and signaling with E. coli was investigated (Figure 7).211−213 The Gal receptor exists on the cell surface, and the

conjugation with DPPE.218,219 Galectin multimerization using glycopolymers has been investigated, and it was found that lactose-substituted glycopolymers in the cell membrane play important roles in galectin-3 multimerization.214 In other research, glycopolymers with GalNAc have been prepared, and it was found that the glycopolymers regulated integrin assembly on the cell surface, which affected cancer cell growth and survival.216 The role of the saccharide has also been investigated using sialic acid modified polymers. PolyMVK was treated with various saccharides, including Sialyl-LacNAc, GD3, and sialyl Lewis X.215 Activation of human natural killer cells (NK) cells was observed to be controlled by the Siglec interaction. A glycopolymer carrying sialic acid was inserted in the cell membrane, and it was found that the interaction of the glycopolymer with Siglec affected the NK cell cytotoxicity. These glycopolymer investigations suggest that multiple sialic acid residues reduce the cytotoxicity of NK cells for cancer cell survival. These results show that glycopolymer technology provides a novel method and an interesting tool to investigate cell functions. There is clear evidence that the addition of certain glycopolymers can control cell viability and functions. This technology has potential in the treatment of cancer and other diseases. These studies are investigated at the level of basic scientific research in vitro, but it is useful to clarify the biological role of saccharides.

Figure 7. Glycopolymer carrying Gal synthesized via ROMP induced clustering of the Gal receptor and chemoreceptor. Clustering of the chemoreceptors suggests intercellular protein interactions.

glycopolymers showed a strong affinity with E. coli because of the multivalent effect with the Gal receptor (lectin) on the cell surfaces. Interestingly, not only lectins on the cell but also other chemoreceptors were affected by the glycopolymers. Lectins on the cell surface interact with other chemoreceptors by inter− receptor communications. The addition of a glycopolymer induced clustering of the lectins and subsequently other chemoreceptors. The migration of the cell was dependent on the DP of the glycopolymer. A single glycopolymer was able to cross-link the lectin and chemoreceptors and induced a motility response and chemotaxis. A fluorescent-labeled glycopolymer to monitor cell behavior has also been prepared. The Bertozzi group synthesized glycopolymers via RAFT living radical polymerization.140−142 The RAFT reagent was conjugated with a phospholipid of 1,2-bis(diphenylphosphino)ethane (DPPE), and poly(methylvinyl ketone) (polyMVK) was prepared by living radical polymerization. Then, saccharides having an aminooxy group were added to polyMVP by a condensation reaction. DPPE-terminated glycopolymers were easily anchored to the cell membrane, which was termed “Glycocalyx engineering” (Figure 8). Glycopolymers with various bioactive saccharides were prepared, and the saccharide function was investigated as an artificial extracellular matrix.214−217 The glycopolymers were inserted in the cell membrane in an extended conformation, because of the

3.3. Glycopolymers for Biosensing

The molecular recognition ability of saccharides can be used as a molecular recognition tool. If the saccharide−protein interaction is strong enough, the interactions can be used to produce bio devices, which function similarly to antibodies. One of the important applications of antibodies is for biosensing and diagnosis; hence, the use of the saccharide− protein interaction in glycopolymers is a promising alternative to antibodies for use in biosensing and diagnosis.220 In addition, saccharides are generally hydrophilic, which inhibits the nonspecific adsorption of protein.221 Biosensors are divided into a sensing part and a molecular recognition unit. The sensing parts are often composed of devices that make use of techniques, such as surface plasmon resonance (SPR), quartz crystal microbalance, field-effect transistor, and other electrochemical techniques. The sensing parts are usually made of substrates, such as gold, semiconductors, and metal nanoparticles. The immobilization of glycopolymers enables biosensing via saccharide−protein interactions. Gold is frequently used as a substrate in biosensing devices. Gold substrates are easily modified by Au−S bond formation. 1680


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Figure 9. Glycopolymer modified gold nanoparticles and application for biosensors: (a) preparation of glycopolymer modified gold nanoparticles via RAFT living radical polymerization and (b) biosensors with glycopolymer modified gold nanoparticles.

polythiophenes with sialic acid had a UV peak at approximately 400 nm, and the addition of influenza viruses (influenza virus A and B) induced a red shift of approximately 10 nm, despite there being no response to the sialic acid recognition lectin. The Bunz group reported accurate lectin and E. coli detection using saccharide-modified poly(p-phenylene ethynylene).234,235 Recently, imaging techniques, such as magnetic resonance and fluorescence have been used for biosensing and diagnosis. The Whittaker group has reported imaging using glycopolymers (Figure 10).236,237 Hyperbranched polymers were synthesized with RAFT living radical polymerization and modified with click chemistry. A 19F label was incorporated with trifluoroethyl acrylate.236 The obtained polymer was used for 19F magnetic resonance imaging. A glycopolymer has also been prepared with magnetic nanoparticles coated with blockglycopolymers carrying Man and Glc.237 The interaction between the glycopolymer and ConA and the cellular uptake of the nanoparticles were monitored by the relaxation times of the magnetic resonance. Pfaff et al. has investigated fluorescent and magnetic imaging with glycopolymer-modified nanoparticles.238 Lu et al. has used fluorescent imaging with BODIPY-labeled glycopolymers carrying Gal.239 Glycopolymer imaging is still in its infancy; however, the magnetic resonance imaging of saccharides has been already applied to biochemical analyses such as brain imaging,240 and glycopolymers are likely to be used as diagnosis tools in the near future. Biosensing is mainly utilized in vitro. Since the saccharide− protein interaction is basically specific, biosensing with saccharides is practical if the interaction is amplified by glycopolymer multivalency. Bioimagings are carried out mainly in vitro and still a little far from practical use in vivo and needs clinical experiments.

As mentioned in section 2.3, thiol-terminated glycopolymers are obtained by RAFT polymerization and degradation of the polymer terminal. We have modified gold substrates and gold nanoparticles with glycopolymers carrying Man, Gal, and GlcNAc and could detect lectins with high affinities by SPR and observed color changes (Figure 9).222,223 The glycopolymers carrying Man (poly(Man-co-acrylamide)) were synthesized by RAFT living radical polymerization, and the polymer terminal was converted to a thiol. The gold nanoparticles were modified by incubation with a polymer solution. Glycopolymermodified gold nanoparticles are optically and electrically active, which is useful for biosensing. The glycopolymer-modified gold nanoparticles showed a pink color with a plasmon peak at approximately 530 nm. The addition of ConA changed the color of the gold nanoparticle solution, and the plasmon peak was red-shifted from 530 to 590 nm because of the crosslinking of the gold nanoparticles. Not only the proteins but also the sugar recognition bacterium (E. coli ORN 178) were able to be detected using glycopolymer-gold nanoparticles.223 On the basis of the color of the gold nanoparticles, glycopolymermodified gold nanoparticles have been used as the biosensor of a lateral flow assay.222,224 The gold nanoparticle has also been used for detection, based on the redox active label from Au(0) to Au3+ using differential pulse voltammetry. We have detected ConA using glycopolymer-modified gold nanoparticles and an electrochemical assay.225 Kitano et al. reported the detection of lectins (ConA and RCA120) using glycopolymers on gold nanoparticles using local SPR.226,227 The Maynard group reported the immobilization of glycopolymer on a gold substrate to analyze the interaction with SPR.228,229 The Narain groups immobilized biotinylated glycopolymer-modified gold nanoparticles on the substrate for detecting interaction of lectins with SPR and diffractive optics technology.230,231 In this review, we mainly focus on glycopolymers synthesized by addition polymerization. However, glycopolymers of πconjugated polymers have been reported for use in biosensing. The Charych group reported various π-conjugated glycopolymers used for biosensing.232,233 Saccharide-modified polydiacetylene (PDA) lipid micelles were prepared by UV irradiation. The UV spectra of sialic acid modified PDA was changed by the addition of the influenza virus, resulting in a red shift and decrease in absorbance. Saccharide-modified polythiophenes have also been investigated by this group. Glyco-

3.4. Glycopolymers for Drug Delivery and Gene Delivery

The interaction of saccharides with specific cells is known, interactions include Gal−hepatocyte, Mal−macrophage, and Glc−cancer cell interactions.4 Glycopolymers have shown early promise as cell specific drug carriers. The Akaike group has demonstrated the hepatocyte-specific uptake of glycopolymers carrying lactose.59 Wang et al. reported drug delivery system based on the interaction with glycopolymer and ASGP-R.241 They reported the doxorubicin delivery encapsulation in the glycopolymer micelles and HepG2 specific delivery via ASGP-R interaction. Chen et al. synthesized the biodegradable 1681


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Figure 11. Cell specific drug delivery with glycopolymer micelles. The block polymer carrying galactose was synthesized by ring opening polymerization, and doxorubicin was adsorbed by hydrophobic interactions. The polymer showed HepG2 specific uptake and drug release.

ymer−nanoparticle also showed pH responsive by degradation at low pH. Glycopolymer having amino group or carboxylic acid group are able to be response to pH. The ionic property of those groups was changed due to the change between amine and ammonium ion or carboxylic acid and carboxylate. Liu et al. reported the block copolymer of poly(2-(diethylamino)ethyl methacrylate)-co-(3-O-methacryloy-glucopyranose)) via RAFT polymerization and pH responsive micelle formation in the acidic condition. 245 Kim et al. reported pH sensitive glycopolymer gel for drug delivery, where the swelling ratio of the polymer was changed by pH.246 Glucose responsive drug carriers have been also reported for insulin delivery for the diabetes patient. The glycopolymer with phenylboronic acid form particles247 or gel248 by the bond formation between hydroxyl group of glycopolymer and phenylboronic acid. The self-assembled particle or gel was decomposed with addition of glucose because of the sequential bond dissociation. Those materials are useful for glucose sensitive drug delivery for the diabetes patient. The Stenzel group also reported the glycopolymer nanocapusules, which are responsive in reductive condition with glutathione.249 They prepared glycopolymer nanocapsules by postpolymerization reaction and investigated the glutathione-specific hydrophilic drug (gemcitabine) release to pancreatic cancer cells. Recently, gene delivery using glycopolymers has also been investigated. Not only the drug with small molecules but also the biomacromolecules of DNA and RNA are important for delivery systems based on the development of gene therapy. Since genes are macromolecules, the design of delivery materials are different from drug delivery. The conjugation of a cationic segment to the glycopolymer is important for complexation with DNA and RNA for gene delivery. The Narain group has studied gene delivery with various glycopolymers in detail, including diblock and random copolymers, and hyperbranched polymers of the glycopolymer

Figure 10. Hyperbranched glycopolymer with a fluorinated segment for MRI-imaging. The polymer was synthesized by RAFT living radical polymerization and click chemistry.

glycopolymer via ring opening reaction and prepared polymer micelles, which attained the hepatoma cell specific delivery of doxorubicin.242 Recent advances in polymer chemistry have enabled the design of drug carriers using glycopolymers. As we described in the previous section, block copolymer of glycopolymers have self-assembling properties to form micelles and vesicles. The size and properties of the polymer carrier affect the drug delivery behavior. The hydrophobic segment can provide a container for the hydrophobic medicines, such as doxorubicin. Hence, block-glycopolymer micelles are useful for cell specific drug delivery (Figure 11).181,243,244 The Armes group has prepared various kinds of self-assembled glycopolymers with hydrophobic segments.178 Several glyco-block copolymers were synthesized, with variations in the ratios of the galactosylated segments and hydrophobic segments and the molecular weights. The self-assembled structures varied from wormlike and spherical micelles to vesicles. Affinity of the wormlike micelles and vesicles with galectin was demonstrated. The glycopolymer vesicles with Gal were biocompatible and enabled intracellular delivery to Human Dermal Fibroblasts (HDF) cells. The environmental responsive materials are required for sophisticated drug delivery systems. The well-known method is the utilization of thermoresponsive polymer of poly(Nisopropylacrylamide). The Stenzel group investigated glucosamine substituted glycopolymer−nanoparticle containing poly(N-isopropylacrylamide), which have shown temperatureresponsive properties for drug delivery.120 The same glycopol1682


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(3-gluconamidopropyl methacrylamide) with a cationic segment (2-amino ethyl methacrylamide) (PAEMA).250,251 DNA formed a complex with the cationic segment of PAEMA by electrostatic interaction. The transfection efficiency was affected by the type of polymer, molecular weight, and monomer ratio. The random copolymer and hyperbranched polymers showed better transfection efficiency because of better uptake to the target cells. The Narain group also showed enhancement DNA transfection using glycopolymer conjugates of gold nanoparticles and carbon nanotubes.252,253 The same group also reported siRNA delivery with cationic glycopolymer, which efficiently exhibited knockdown of cell growth factor EGFR.254 The Obata group reported gene delivery systems with glycopolymer having Man.255,256 They prepared poly(2-(α-Dmannnopyranosyloxy)ethyl-co-(2-dimethylaminoethyl methacylates)), which showed the affinity to ConA and the DNA condensed ability. The same group also reported the overall transfection efficiency of block and statistical copolymer and found the statistical copolymer showed the better transfection efficiency. The polymer micelles are one of the prominent materials for drug delivery and gene delivery. Though most of the experiments were still at the basic level and need more research, target specific and stimuli responsive delivery systems are expected to be of practical use in the near future.

Figure 12. Glycopolymer conjugation to proteins: (a) polyvalent trehalose-substituted protein for resistance to heat shock and (b) polyvalent antigenic carbohydrate for amplification of the immune response.

3.5. Glycopolymer Conjugation to Biomacromolecules

New types of biomolecules are able to be fabricated by conjugation of glycopolymers to other biomacromolecules. In section 3.2, we described glycopolymer conjugation to the cell membrane as an artificial extracellular matrix. Glycopolymers synthesized via living polymerization are easily modified at the polymer terminal, and the glycopolymer terminal is able to be conjugated to proteins. Biotin-terminated RAFT and ATRP initiator reagents have been used to synthesize glycopolymers conjugated with streptavidin.228−231 The glycopolymers with biotin also bound to proteins, substrates, and nanoparticles.257,258 Gupta et al. conjugated glycopolymers to virus capsid proteins,259 where glycopolymers were prepared via ATRP and the polymer conjugated with click chemistry and the virus-glycopolymer conjugates exhibited a new method to prepare uniform nanocapsules.238 The Maynard group has conjugated a trehalose glycopolymer to a protein (Figure 12a).260,261 The glycopolymers were synthesized by RAFT polymerization, and the polymer was conjugated to lysozyme by disulfide bond formation. Due to the trehalose activity and multivalency, the lysozyme with trehalose showed stability to heat shock. Conjugation of saccharides to a protein has advantages in terms of the immune response. Since saccharides are involved in diseases and cancer, immunization using saccharides is important in view of production of antibodies. However, the immunogenicity of saccharides is generally weak, and amplification of the immune response is indispensable. Bundle et al. conjugated glycopolymers with albumin, which amplified the immune response (Figure 12b).262 Glycopolymers carrying β-mannan trisaccharides with polyacrylamide were prepared, and the polymer was conjugated with chicken albumin, which was then used for immunization in mice. The glycopolymer conjugate showed a robust and strong immune response, which was advantageous for antibody production. A glycopolymer with tetanus toxin has also been prepared, which also induced a strong immune response. The Haddleton group has prepared a

glycopolymer conjugate with bovine serum albumin using a maleimide-terminated glycopolymer, which induced an immune response.263 A glycopolymer with gold nanoparticles has also been reported to show a strong immune response because of the multivalency of the polymer.264 The amplification of immunogenicity using glycopolymers is a new target for vaccine development. DNA can be used in nanotechnology for the creation of DNA origami.265 Matsuura et al. conjugated welldefined glycopolymers with DNA and controlled the affinity using DNA technologies.266,267 Glycopolymer conjugates with DNA were prepared having half-zip structures, which were incubated with a DNA platform to construct well-defined glycopolymer brushes, which showed strong interactions with lectins.

4. CONCLUSION AND OUTLOOK This review has outlined the technology for the use of glycopolymers nanotechnology for biotechnology application. Much attention to the application of saccharides in medicines and biomaterials has been paid, as there is the potential for the development of novel medicines, drug-delivery systems, antibodies, and biomaterials. The bottleneck in the application of saccharides is the weak interaction of saccharides in the monomeric state, but this can be amplified by the presence of multivalency. However, the process of molecular recognition by saccharides is not totally clear, and the precise preparation of multivalent saccharides is important for future application of saccharides in nanomedicine. The living polymerization of glycopolymers is important to control the preparation of multivalent glycoclusters. Glycopolymers synthesized via living radical polymerization enable the design of specific polymers with a multivalent effect and conjugation to proteins and other materials, which is indispensable for the development of glycopolymer nanomedicine. The physical properties of glycopolymers are also important to control the self-assembling structure of polymer micelles and particles. Advances in 1683


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glycopolymer are the key for the practical application of saccharide science.

was appointed Associate Professor. His research is focused on the development of general procedures to create synthetic polymer nanomaterials that function as antibody and enzymes.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Tel: +81-92-8022749. Notes

The authors declare no competing financial interest. Biographies

Dr. Hirokazu Seto received his Doctor degree of Engineering in 2011 from Saga University. In the same year, he joined Prof. Miura’s group in Kyushu University. In 2013, he became a Researcher of Japan Society for Promotion of Science (JSPS) Research Fellowships. His research interest is chemical engineering with glycopolymer technologies and polymeric catalysis.

ACKNOWLEDGMENTS We are grateful for the financial support provided by the Grantin-Aid for Scientific Research B (15H03818), and Challenging Exploratory Research (26620106).

Yoshiko Miura is currently Professor at Kyusyu University. Yoshiko Miura received her B Eng. Degree in 1995 and M Eng. Degree in 1997 from the Kyoto University under the supervision of Professor Yukio Imanishi. She received Dr Eng. Degree in 2000 from the Kyoto University under the supervision of Professor Shiro Koabayashi. She spent her postdoctoral period from 2000 to 2001 at the University of Pennsylvania in Professor Virgil Percec’s group. In 2001, she joined the Department of Molecular Design and Engineering, Nagoya University, as Assistant Professor and started the research of glycomaterials with Professor Kazukiyo Kobayashi. In 2005, she was appointed Associate Professor at the Schools of Materials Science in Japan Advanced Institute of Science and Technology. In 2010, she was appointed Professor at the Department of Chemical Engineering, at Kyushu University. Her research interests are biomaterial fabrication with glycopolymers and glyco-nanoparticles.

ABBREVIATIONS ASGP-R asialoglycoprotein receptor ATRP atom transfer radical polymerization Cer ceramide ConA concanavalin A DC-SIGN dendritic cell-specific ICAM-grabbing non-integrin E. coli Escherichia coli FET field-effect transistor Gal galactose GAMA 2-gluconamidoethyl methacrylate GalNAc N-acetyl galactosamine Glc glucose GlcNAc N-acetyl glucosamine HDF human dermal fibroblasts LacNAc Gal(β1−4) GlcNAc LAMA 2-lactobionamidoethyl methacrylate LSPR local surface plasmon resonance Man mannose MVK methylvinyl ketone Neu5Ac N-acetylneuraminic acid, sialic acid NK human killer cells PAMAM polyamidoamine PDA polydiacetylene PNA peanut agglutinin PVLA poly(N-p-vinylbenzyl-D-lactonamide) QCM quartz crystal microbalance RAFT reversible addition fragment chain transfer RCA Ricinus communis agglutinin SET-LRP single-electron transfer living radical polymerization SI-ATRP surface-initiated atom transfer radical polymerization SNA sumbucus nigra lectin

Dr. Yu Hoshino was born in Kanagawa Prefecture, Japan, in 1978. He received his Doctor degree in 2006 from Tokyo Institute of Technology under the supervision of Professor Yoshio Okahata. He spent his postdoctoral period from 2006 to 2010 at the University of California, Irvine, in Professor Kenneth J. Shea’s group, and began the study of nanoparticle−peptide interaction. In 2010, he joined the Department of Chemical Engineering, Kyushu University. In 2013, he 1684


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surface plasmon resonance 2,2,6,6,-tetramethylpieperidine 1-oxy

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