Sequence and Architectural Control in Glycopolymer Synthesisbecergroup.sems.qmul.ac.uk/publications/papers/becer_085.pdf · containing macromolecules, are able to mimic structural

REVIEW

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Sequence and Architectural Control in Glycopolymer Synthesis

Yamin Abdouni, Gokhan Yilmaz, and C. Remzi Becer*

DOI: 10.1002/marc.201700212

areas of lectins, of modulating the inter-actions with other biomolecules, and of affecting the rate of biological processes, which in turn involves conformational changes due to their very sensitive sugar coding.[21,22] This special sugar coding system allows them to have crucial bio-logical roles with unusual oligosaccha-ride sequences, unusual presentations of common terminal sequences, and even modifications of the sugars them-selves.[23,24] Hence, even though at pre-sent there has been great progress on the synthesis of well-defined glycopolymers and glyconanoparticles, there is still a demand for a precise control on monomer sequences, compositions, and architec-tures in order to understand the nature of the carbohydrate-lectin interaction in more details.

During the last decade, there has been a great deal of interest in the integration of carbohydrates in nanotechnology.[25–28] Advances in glyconanotechnology have allowed for the creation of different bioactive glyconanostructures for various medical applications such as drug delivery, gene therapy, pathogen detection, toxin inhibition, and the development of lectin-based biosensors.[29–32] Nanoparticles functionalized with carbohy-drates present a vehicle with high multivalency for lectin inter-actions and allow increased local concentrations of ligands on a relatively small surface.[33,34] Glyconanoparticles, as carbohy-drate-based systems, provide a controlled platform for glycobio-logical studies because of their ability to mimic the behaviour of the naturally existing glycocalyx.[34] Therefore, the molecular design and engineering of highly innovative glyconanoparticles with unique physiochemical properties will help the further enhancement of specific recognition properties on multivalent scaffolds.

In the last couple of years, “single chain technology” has been explored for a deeper understanding of the multivalent func-tions and the precise folding mechanism of naturally occurring single-chain architectures of macromolecules in biological sys-tems, such as secondary and tertiary structures of proteins and enzymes.[35–37] In nature, many biomolecules exhibit reversible self-folding processes that are necessary for interfacial mole-cular recognition.[38,39] Therefore, the introduction of precision in synthetic single polymer chain folding is an important step forward towards the creation of more complex macromole-cules with specific functionalities with the aim of imitating complex biological systems. Not only polymer chemists are interested in developments in single-chain collapse, but also

Glycopolymers

Glycopolymers are synthetic-carbohydrate-containing materials capable of interacting and binding to specific targeting lectins, which are crucially impor-tant in many biologically active processes. Over the last decade, advances in synthetic chemistry and polymerization techniques have enabled the develop-ment of sequence and architecturally controlled glycopolymers for different types of bioapplications, such as drug delivery and release purposes, gene therapy, lectin-based biosensors, and much more in the future. These preci-sion glycopolymers are able to mimic structural and functional features of the naturally existing glycocalyx. Furthermore, self-assembled glycopolymers could enhance specific and selective recognition properties on multivalent scaffolds in glycoscience. This mini-review will focus on production methods and recent advances in precision synthesis and self-assembly of glycopoly-mers. Additionally, possible contributions of single-chain folding in glycopoly-mers will be discussed as a future prospect.

Y. Abdouni, Dr. G. Yilmaz, Dr. C. R. BecerSchool of Engineering and Materials ScienceQueen Mary University of LondonLondon E1 4NS, United KingdomE-mail: [email protected]

1. Introduction: Glycopolymer–Lectin Binding

Multivalent protein-carbohydrate interactions play a pivotal role in a wide range of complex biological processes, such as inter-cellular recognition, signal transduction, and host-pathogen recognition.[1–5] Carbohydrates exhibit a great interaction capacity to specific proteins owing to their monomeric struc-tures and highly branched nature.[6–8] This specific interaction is greatly enhanced by the multivalency effect of densely packed carbohydrate molecules with unique functionalities, which is known as the “glycocluster effect”.[9,10] The interactions between carbohydrates and lectins are based on hydrogen bonding, van der Waals’ interactions, and hydrophobic stacking at the mole-cular level.[11,12] In contrast to other types of proteins, lectins are not products of the immune system and they display a great diversity in terms of their molecular structure and size.[13–15] Glycopolymers, which are essentially synthetic-carbohydrate-containing macromolecules, are able to mimic structural and functional features of oligosaccharides thanks to variations in anomeric status, linkage positions, branching, and introduc-tion of site specific substitutions.[16–20] A wide range of oligosac-charides have the capability of covering functionally important

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researchers from various other areas, especially those in biology and medicine. Biologists are following up this field of research closely, as controlled folding of macromolecules may enable the manipulation of biochemical reactions.[40–42] In light of these developments, single-chain folding of glycopolymers was dis-cussed as a future prospect in the last part of this review.

2. Sequence-Controlled Glycopolymers

Until recently, glycopolymer synthesis was mainly limited to the synthesis of homomultivalent, sugar-containing polymers. In the last couple of years, polymer chemists have focused on achieving absolute control over monomer sequence. Unlike for peptide synthesis, polymer synthesis had not been established in a sequence-controlled manner up until now. New methods have been developed that enable excellent control over primary and secondary structures in polymer design. This is no dif-ferent in glycopolymer design, where it is believed that better control over glycopolymer architecture will not only lead to a better lectin binding affinity, but will also introduce a much desired selectivity towards specific lectins. That improved con-trol over architecture has significant influence on glycopolymer binding has already been demonstrated by the development of star glycopolymers, which was shown to bind better to spe-cific lectins compared to their linear counterparts.[43,44] Various research groups have contributed to this emerging field of precision glycopolymer synthesis in diverse approaches.

In 2013 Barner-Kowollik et al. described several approaches to acquire sequence-controlled polymers.[45] Three different approaches were suggested, providing a degree of sequence control (Scheme 1a–c). The first approach consisted of the classical step-by-step synthesis yielding sequence-defined poly-mers, which are often prepared on solid-phase. The second approach relies on classical reversible-deactivation-based syn-thesis of block copolymers, which consists of the sequential polymerization, with isolation of intermediate polymers, of sequentially added monomers. Thirdly, they demonstrated the sequence-controlled polymerization of different monomers in a one-pot process, without isolation steps via time-regulated chain extensions. Two other approaches for the synthesis of periodic polymers that contain a sequence defined periodic rep-etition of monomers can be added to the list (Scheme 1d–e). The fourth approach would be the polymerization of a defined oligomer into a polymer with repeated sequence, which is often observed in nature (e.g., glycosaminoglycans, collagen, etc.). The fifth approach would consist of the combination of one or multiple orthogonal reactions, either for the polymerization or post-polymerization modification of a polymer, resulting in a macromolecule with a repeated sequence.

2.1. Sequence-Defined Glycooligomers

This first approach was first introduced in glycopolymer syn-thesis by the group of Hartmann, who elegantly utilised standard peptide synthesis coupling procedures and combined with click reactions. In order to achieve these solid-phase bound oligomers, different building blocks had to be prepared

(Scheme 2). The group designed various blocks using a doubly protected diethylenetriamine key intermediate as an asymmet-rical precursor capable of being functionalized at the secondary amine.[46–48]

At first, homomultivalent glycooligomers presenting man-nose were synthesized via an on-resin 1,3-dipolar cycloaddition to a scaffold composed of these building blocks (Scheme 3).

Yamin Abdouni received his bachelor’s degree in chemistry in 2014 at Ghent University (Belgium) and his master’s degree in chemistry at the same university in 2015. He moved to the United Kingdom to under-take a PhD at Queen Mary University of London under the supervision of Dr. Remzi Becer. The main focus of his

research is on the development of novel glycopolymers with controlled sequence and architecture.

Gokhan Yilmaz studied Chemical Engineering at Hacettepe University in Turkey. He completed his PhD on the synthesis of glycomaterials for multi-valent interactions at the University of Warwick under the supervision of Prof. David Haddleton and Dr. Remzi Becer. He is now a postdoc-toral research assistant in

the School of Engineering and Materials Science at Queen Mary University of London. His research is focused on the preparation of well-defined bioactive glyco-polymers/nano-particles for various biological applications.

C. Remzi Becer graduated in 2005 from the Istanbul Technical University, Turkey. He completed his PhD (2009) in the group of Prof. Schubert at Eindhoven University of Technology, the Netherlands, and Friedrich-Schiller-University of Jena, Germany. In 2009, he joined the group of Prof. Haddleton, University of Warwick, UK, and then

started his independent research group at the University of Warwick in 2011. He is a Senior Lecturer in the School of Engineering and Materials Science at Queen Mary University of London.




These mannose-containing oligomers could show that binding affinity towards the lectin Con A was not only dependent on the number of presented sugars on the scaffold, but also on chem-ical composition of the scaffold and the spacing in between the ligands.

After the successful synthesis of these homomultivalent gly-cooligomers, more diverse heteromultivalent glycooligomers were prepared, presenting different combinations of Man, Gal, and Glc with a controlled number and position of ligands. These glycooligomers were further subject to evaluation for their binding behaviour towards the lectin Con A.[49] More interestingly, perhaps, was the combination of these building blocks with a new photoswitchable building block containing an azobenzene moiety.[50] Use of this building block provided a controlled reduction in binding affinity upon E → Z photo-isomerization towards PA-IL, a tetrameric, calcium-dependent lectin, which specifically binds to α-galactosides.

The same principle of building blocks combined with click reactions was further explored using an in-flow conjugation of

thioglycosides to a double-bond-presenting diethylenetriamine precursor via thiol-ene chemistry.[48] The main difference here is that the building blocks were functionalized with glycosides prior to the solid phase synthesis. After glycosylation, these pro-tected carbohydrate-containing building blocks were coupled to the solid-phase, resulting in monodisperse sequence-defined glycooligomers with different glycosylation patterns.

The same group has also brought this approach one step forward using a combination of solid phase synthesis and step-growth polymerization by photoinduced thiol-ene coup-ling.[51] Firstly, two sets of macromonomers were prepared via solid phase assembly of functional building blocks, intro-ducing either a hydrophilic spacer block with thiol end groups or sugar-presenting blocks with varying number of sugar units in the side chain and alkene end groups. Subsequently, as seen in Scheme 4, photoinduced thiol-ene coupling step-growth poly merization were undertaken to obtain specifically sequence-controlled glycopolymers with high molecular weight. Obviously, this advanced approach will lead to the synthesis of


Scheme 1. a) Classical step-by-step synthesis of sequence-defined polymers. b) Sequential polymerization (with isolation of intermediate polymers) of sequentially added monomers. c) Sequence-controlled polymerization via time regulated chain extensions, without the need for isolation steps. d) Polymerization of a sequence-defined oligomer into a periodic polymer. e) Post-polymerization modification via orthogonal reactions resulting in a periodic polymer.



precision glycopolymers with higher molecular weight multi-block copolymers for polymer chemists in this field.

2.2. Sequence-Control via Time-Regulated Additions

Although solid-phase polymer synthesis allows for an absolute control over glycopolymer sequence and allows for the synthesis of monodisperse polymers, the fact that synthesis occurs on a solid-phase limits the application of this method on a larger scale. In 2007 Lutz et al. published a report in which they described a kinetic strategy allowing control over microstructure in radical chain-growth polymerizations.[52,53] The method relies on the time-regulated sequential addition of N-substituted maleimides

during the chain-growth poly merization of styrenes. The great difference in monomer reactivity renders it possible to incorpo-rate the maleimides at specific places along the polymer chain. In 2013, the group further used this technique for the synthesis of single-chain sugar arrays (Scheme 5). They polymerized three different triple-bond-containing maleimides, each containing protecting groups of different lability, allowing for the selective deprotection of each set of monomers.[54] After each deprotec-tion step, different azide-functionalized hexoses were clicked to the polymer backbone. The method demonstrated that sugars could be placed at certain locations along a bioinert polystyrene backbone. Although this proposed technique does not deliver monodisperse sequence-defined glycopolymers, it does allow the synthesis of sequence-controlled polymers on a larger scale.


Scheme 2. Building block synthesis. Reproduced with permission.[46] Copyright 2012, American Chemical Society.

Scheme 3. Solid-phase synthesis of glycopolymer segments. Reproduced with permission.[46] Copyright 2012, American Chemical Society.



2.3. Sequence Control via Time-Regulated Chain Extensions

This first use of controlled radical polymerizations showed great potential in the development of sequence-controlled gly-copolymers and was thus further exploited. Controlled radical polymerizations offered not only better polydispersities during chain growth, but copper-mediated radical polymerizations also

introduced a much better chain-end fidelity. This increased chain-end fidelity inspired Haddleton et al. for the synthesis of sequence controlled glycopolymers via copper(0)-mediated living radical polymerization (Cu(0)-LRP), as developed by Percec et al. in 2002.[55–57] The group made use of the retention of the chain end to perform chain extensions after mono mer consumption (Scheme 6). Sequential addition of new mono mer

after consumption of each block provided sequence-controlled block copolymers of well-defined length and with low dispersities.

This route was employed for the prepa-ration of a whole range of different gly-copolymers based on acrylate monomers containing sugar units synthesized via the 1,3-dipolar cycloaddition. These glycopoly-mers, containing mannose, glucose and fucose moieties, were examined for their binding behaviour towards the Dendritic Cell-Specific Intercellular adhesion mole cule-3-Grabbing Non-integrin (DC-SIGN), a lectin highly present on dendritic cells. Higher-affinity binding was observed for polymers with a higher mannose content, although no effect of sequence on binding was reported.

The use of Cu(0)-LRP for the preparation of sequence controlled glycopolymers was further adopted in combination with other ‘click’-like reactions. In this case, Haddleton et al. synthesized a sequence controlled pre-polymer that could selectively be glycosylated at different places.[58] The prepolymer was synthesized using the epoxide-containing gly-cidyl acrylate and TMS-protected propargyl acrylate. A post-polymerization modification


Scheme 4. Schematic presentation of the solid phase synthesis of end-functionalized macromonomers using tailor-made building blocks (left) and their step-growth polymerization via thiol-ene coupling (right). Reproduced with permission.[51] Copyright 2017, American Chemical Society.

Scheme 5. General strategy for the synthesis of single-chain sugar arrays. Reproduced with permission.[54] Copyright 2013, John Wiley & Sons, Ltd.



was carried out via thiol-halogen reactions using 1-thio-β-D-glucose tetraacetate. After this, the TMS group was deprotected and subsequently the free triple bonds were used for conjuga-tion of azide-functionalized mannose.

Qian et al. made use of sequential Atom Transfer Radical Polymerization (ATRP) for the synthesis of triblock-copoly-mer-grafted silica microparticles.[59] First, the authors immo-bilized ATRP initiators on the surface of the silica particles and afterwards the glycopolymers were grown on that surface (Scheme 7). Unlike the previous approach (using Cu(0)-LRP), the silica particles were isolated and washed in between the

poly merization of each block. The glycopolymer-grafted silica particles were then further used for efficient and selective enrichment of glycopeptides.

2.4. Sequence Control via Orthogonal Reactions

Lastly, the fourth approach was applied by Chen et al.[60] The group first prepared polymethacrylic acid via the RAFT poly merization process. Subsequently, the free pending acid groups were used in an Ugi reaction with gluco- or mannosa-

mine, incorporating a first sugar into the chain, and propargyl isocyanoacetamide, which tactfully introduced a terminal alkyne. These terminal alkynes were then finally employed to click gluco- or mannosyl azide onto the polymer chain (Scheme 8).

Although in the last couple of years the main focus of poly mer chemistry has been the precise control over monomer sequence, this cannot really be extended towards gly-copolymers, for which the field is still in its infancy. Few research groups have currently attempted to tackle this problem, and each technique comes with its advantages and drawbacks. Perfect monodisperse sequence-defined polymers could readily be achieved via solid-phase glycopolymer synthesis; how-ever, multiple steps are required to achieve only small amounts of product. Keeping that in mind, chain growth polymerization could be favoured. Lutz et al. demonstrated that sequence controlled glycopolymers can be achieved based on a difference in monomer reactivity. However, also in this case several


Scheme 6. Schematic representation of the synthesis of multiblock glycopolymers by sequential addition of glycomonomers at defined periods of time via Cu(0)-LRP. Reproduced with permission.[55] Copyright 2013, John Wiley & Sons, Ltd.

Scheme 7. Schematic overview of the preparation of triblock copolymer-grafted silica microparticles by sequential-ATRP. Reprinted with permission.[59] Copyright 2015, American Chemical Society.



deprotection steps are required for the post-polymerization gly-cosylations. Chain extensions via copper-mediated polymeriza-tions seem very promising, as these techniques can easily be scaled up and occur in a one-pot manner. Although there is a good control over sequence of the block copolymer, each block still has a distribution, and in this aspect it is still inferior to the solid-phase synthesis approach regarding ‘control’. How-ever, the dispersities of the blocks are relatively low, allowing for a well-controlled synthesis on a bigger scale.

3. Self-assembly of Glycopolymers

Recently, it has become more and more clear that presenta-tion of the saccharide units is of great importance in achieving enhanced lectin-glycopolymer binding. Glyconanoparticles with different morphologies can readily be obtained depending on the hydrophilicity/hydrophobicity and the length of the dif-ferent blocks in the block copolymer which have an effect on the packing parameter.[61–63] Over the past decade, a whole range of different self-assembling glycopolymers have been synthesized and their composition and presenting morpholo-gies have been greatly summed up in a review by Chen et al.[64] In this section, different methods will be summarized for the preparation of these assemblies, along with most important and recent publications.

3.1. Self-Assembly Based on Amphiphilicity

The synthesis of glycopolymeric amphiphiles was first reported in 1999 by Li et al.[65] The authors prepared a set of block copoly-mers based on polystyrene-b-poly[2-β-D-glycopyranosyloxy)ethyl acrylate]. By varying the composition, the solvent, and the con-centration, they were able to prepare different morphologies ranging from spherical micelles to cylindrical micelles and vesicles called polymersomes. Now, more than 15 years later, many articles have been published on the synthesis of different amphiphilic glycopolymers, each one differing either in choice

of the hydrophobic block, choice of the sugar, and/or of course the polymerization procedure.[64,66–70]

In the last few years, one of the most active groups working on glycopolymer self-assemblies and their use in biomedical applications is undoubtedly the group of Stenzel. The group prepared several glycopolymers via different methods. In 2014 the group published a collaborative report with the group of Du Prez, where they elegantly used the thiolactone strategy devel-oped by Espeel et al. (Scheme 9).[71] The authors firstly prepared a statistical copolymer of N-isopropyl acrylamide and N-homo-cysteine thiolactone acrylamide. The glycopolymers were pre-pared by using a one-pot procedure in which the thiolactone ring is opened by an aliphatic amine, which releases a thiol that was subsequently reacted with a bromine-functionalized sac-charide already present in the reaction mixture. The size of the obtained particles after dialysis could be tuned by varying the length of the amine side chains.

Another strategy in which the group managed to tune gly-copolymer morphology was using two sets of block copoly-mers and simply changing the mixing ratio (Scheme 10).[72] Two sets of block copolymers were prepared, the first based on mannose acrylate and butyl acrylate. For the second, man-nose acrylate was replaced by oligo(ethylene)glycol methyl ether acrylate (OEGMEA, Mn = 480 g mol−1). It was observed that glycopoly mer morphologies with higher mannose content had better cellular uptake, which suggests that mannose con-centration is more important than shape and size effects. The same group furthermore prepared biodegradable glycopolymer micelles as drug delivery platforms via RAFT.[73] In order to achieve biodegradability in the glycopolymer block, a 5,6-benzo-2-methylene-1,3-dioxepane (BMDO) monomer was copolymer-ized, which introduced cleavable ester bonds.

Zentel et al. employed active esters for the preparation of poly mersomes forming block-glycopolymers.[74] The hydro-phobic block of the copolymer consists of a statistical copoly mer of lauryl methacrylate and 2-(2,2-dimethyl-1,3-dioxolane-4-yl)-ethyl methacrylate. The incorporation of the last monomer provides a controlled pH responsive disintegration of the poly-mersomes, which can be used for controlled cargo release.


Scheme 8. Modular synthesis of glycopolymers via Ugi reaction and click chemistry. Adapted with permission.[60] Copyright 2016, Royal Society of Chemistry.



The group of Lecommandoux published several papers on the synthesis and self-assembly of amphiphilic glycopolypep-tides.[75] Their approach was first introduced using two oligo-saccharides, dextran or hyaluronan, as the hydrophilic block combined with poly(γ-benzyl-L-glutamate) as the hydrophobic block (Scheme 11).[76] Tree-like structures were prepared via the Huisgen cycloaddition reaction of an azide-functionalized oligosaccharide and alkyne-functionalized small propargylgly-cine block. Another strategy they employed was again the use of a block copolymer consisting of poly(γ-benzyl-L-glutamate) and polypropargylglycine.[77] Here, the alkynes were clicked to

azide-functionalized iminosugars. The obtained glycopolypep-tides were capable of self-assembling, but the polymers did gen-erate the tree-like structure. In a recent publication, the authors synthesized glycopolypeptides containing galactose based on the same principles.[78]

Apart from varying the block lengths, Satoh et al. prepared a range of miktoarm block copolymers to obtain different gly-copolymer morphologies.[79] A series of different miktoarm polymers was prepared in which the amount of arms per block was changed; this altered the packing parameter, resulting in a change in micelle size. The miktoarm polymers were prepared

by clicking alkyne-functionalized malto-heptaose using the copper-catalyzed azide–alkyne cycloaddition to azide-functionalized poly-ε-caprolactones.

An interesting approach was used for the synthesis of gradient glycopolymers by Wei et al.[80] The group made use of the in situ enzymatic monomer transformation using Novozym 435. Gradient glycolymers were prepared via the RAFT polymerization of 2,2,2-trifluoroethyl methacrylate (TFEMA) (Scheme 12). The presence of Novozym 435 and 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose resulted in the gradual conversion of TFEMA into 1,2:3,4-di-O-isopropylidene-6-O-methacryloyl-α -D-galactopyranose (DIMAG) in the reaction medium, delivering a gradient glycopoly mer as a final product. Comparison of the binding affinity of these galactose-containing


Scheme 10. Synthetic pathway for the preparation of glyco-nanoparticles with different mor-phologies. Reproduced with permission.[72] Copyright 2015, Royal Society of Chemistry.

Scheme 9. One-pot reaction pathway to glycopolymer-based nanoparticles, employing a double modification (aminolysis and nucleophilic substitu-tion) of thiolactone-containing polyacrylamides. Reproduced with permission.[71] Copyright 2014, John Wiley & Sons, Ltd.



block-, gradient-, and statistical glycopolymers showed that binding affinity towards the lectin RCA120 was optimal for the glycopolymer with the block structure. The use of concurrent RAFT poly merization and enzymatic monomer transforma-tion was further used by the group of Tao for the synthesis of a multi functional glycopolymer.[81]

Self-assembly was also observed by Böker et al. for double-hydrophilic glycopolymers consisting of poly(hydroxyethyl acrylate) (PHEMA) and an N-acetyl glucosamine monomer (Scheme 13).[82] The authors state that although their PHEMA block should have a cloud point of at least 32 °C and thus be water soluble, they still obtained formation of spherical nanoparticles.

3.2. Temperature-Triggered Self-Assemblies

Instead of using hydrophobic blocks in the design of the block copolymer, several research groups have opted to use double hydrophilic blocks in which the non-saccharide block is a hydrophilic thermoresponsive block. Upon heating of the dis-solved polymers in water, often based on poly(diethylene glycol

methacrylate) (PDEGMA) and poly(N-iso-propylacrylamide) (PNIPAM), the particles aggregate due to the LCST behaviour of the aforementioned polymers. In 2008 Alexander et al. prepared block copolymers of PDEGMA and poly(2-glucosyloxyethyl methacrylate) via several controlled radical polymerization techniques.[83] By changing the temperature above or below the LCST of the PDEGMA, the authors were capable of controlling the size of the obtained vesicles. PDEGMA was further used by Stenzel and collaborators for the synthesis of thermoresponsive micelles first in combination with thiol-ene ‘click’-like chemistry and further in combination with copper-catalysed azide–alkyne ‘click’ chem-istry (Scheme 14).[84,85]

Haddleton et al. further employed the novel aqueous SET-LRP for the synthesis of

their double-hydrophilic block copoly mers.[86] Rapid dispropor-tionation of CuBr allows for a fast polymerization with high conversions. Diethylene glycol ethyl ether acrylate (DEGEEA) was polymerized in combination with mannose acrylate, yielding well-defined polymeric nanoparticles above the LCST.

The other commonly used polymer with LCST behaviour, PNIPAM, was also employed for the synthesis of thermorespon-sive glycopolymers. Zhu et al. prepared triblock glycopolymers consisting of two blocks of PNIPAM and a glucose-containing block via RAFT.[87] In addition, these polymers were further capable of self-assembling. The use of PNIPAM was further employed in combination with an adamantane-containing block by Becer et al. (Scheme 15).[88] The Adamantine® adamantane blocks were subsequently made more hydrophilic using the supramolecular interaction of adamantane and β-cyclodextrins decorated with mannose units in water.

3.3. pH-Responsive Self-Assemblies

A potential interesting feature, especially in regards to drug release, would be the integration of pH-responsive blocks con-

trolling the self- and disassembly of block-glycopoly mers. Armes et al. first reported the synthesis of these pH-responsive glyco-polymers in 2003.[89] The group synthesized different triblock glycopolymers via ATRP based on poly(ethylene oxide) (PEO) and two different sugar monomers: 2-glucona-midoethyl methacrylate (GAMA) and 2-lacto-bionamidoethyl methacrylate (LAMA). The pH-sensitive blocks were composed of 2-(diethylamino)ethyl methacrylate (DEA) or 2-(diisopropylaminoethyl methacrylate (DPA). Self-assembly of glycopolymers could be triggered by changing the acidity below or above pH 7. The same GAMA monomer was further employed by Dong et al. for the fabrication of star-shaped poly-peptide/glycopoly mer biohybrids composed


Scheme 11. Oligosaccharides coupling onto poly(γ-benzyl-L-glutamate)-block-poly-(propargylglycine) by Huisgen cycloaddition. Reproduced with permission.[76] Copyright 2012, Royal Society of Chemistry.

Scheme 12. One-pot synthesis of the gradient glycopolymer via concurrent enzymatic mono mer transformation and RAFT polymerization. Reproduced with permission.[80] Copyright 2014, American Chemical Society.



of poly(γ-benzyl L-glutamate).[90] By using G0-PAMAM as a core and by varying the pH, the size of the produced micelles could be tuned. Another group used dendronized lysine for this purpose.[91]

On the other hand, Wang et al. produced pH-sensitive block glycopolymers of poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) and poly(3-O-methacryloyl-a,b-D-glucopyranose) (PMAGlc) via RAFT.[92] Spherical micelles were formed with PDEAEMA as the hydrophobic cores and PMAGlc as the hydro-philic shells in alkaline aqueous solution (Scheme 16).

Not only can dis- or self-assembly can be triggered, but also changes in various self-assembling morphologies can be achieved using pH-sensitive blocks. Change of morphology was obtained by Stenzel et al. based on a single triblock- copolymer of poly(2-acryloylethyl-α-D-mannopyranoside)-b-poly(n-butylacrylate)-b-poly(4-vinylpyridine) (PAcManA70-b- PBA369 -b-PVP370).[93] The obtained morphologies were quite interesting, ranging from flower-like micelles, cylindrical micelles, raspberry-like morphologies, to nanocaterpillars, all depending on the processing conditions (pH of the aqueous environment during dialysis) (Scheme 17).

3.4. Self-Assembly based on Electrostatic Interactions

Ionic interactions are the strongest non-covalent inter-actions and can thus form a strong basis for the self-assembly or loading of glycopolymeric nanoparticles. Narain et al. achieved nanoparticles by using the electrostatic interaction of negatively charged plasmid DNA and a cationic block-glycopoly mer consisting of 3-gluconamidopropyl meth-acrylamide and 3-aminopropyl methacrylamide.[94] Wang et al. furthermore used a diblock glycopolymer consisting of 2-(methacrylamido) glucopyranose and methacrylic acid mono-mers synthesized via RAFT in combination with a quaternary ammonium chitosan as a crosslinker (Scheme 18).[95] Optimi-zation of the synthesis conditions resulted in the formation of glyconanogels with a compact ionic cross-linked core and a glu-cose corona, as was confirmed by TEM.

Chen et al. first synthesized a copolymer with dopamine and amino groups that were capable of self-assembling with zinc phthalocyanine into stable nanoparticles (Scheme 19).[96] These positively charged nanoparticles were then further complexed with the same block glycopolymer used by Wang et al., yielding

glycopolymer decorated nano-phthalocyanine nanoparticles.

Although many different self-assembling glycopolymer structures have been achieved over the past two decades, the number of architectures is still limited, ranging from micelles to polymersomes for diblock based glycopolymers. More interesting structures could be achieved by using triblock copoly-mers, as evidenced vide supra; however, gly-copolymer–lectin binding affinity showed to be more influenced by the density of the sugar ligands than the overall glyco-polymeric architecture. Looking to nature, these types of self-assembled architectures can be found on the scale of cells and orga-nelles. Selectivity and specificity, however, occur on the scale of proteins and recep-tors embedded in these nanostructures. It has become clear that in order to achieve the selectivity and specificity often observed in nature, control should be performed on the smallest scale possible. As illustrated in the first section, control over primary


Scheme 14. Synthetic strategies for the preparation of glucose-functionalised (co)polymers. (B1) HEMA, AIBN, DMAc, 70 °C; (B2) AIBN, toluene, 80 °C; (B3) 4-pentenoic anhydride, DMAP, pyridine, DMF; (B4) UV, glucothiose, DMPA, DMF. Reproduced with permission.[84] Copyright 2009, Royal Society of Chemistry.

Scheme 13. General scheme for the synthesis of PHEMA-b-PGlcNAcEMA. Reproduced with permission.[82] Copyright 2015, Royal Society of Chemistry.




structure is possible, but what differs in comparison to natural glycosylated proteins is the absence of controlled single-chain folding.

4. Single-Chain Folding of Glycopolymers: The Next Generation

Single-chain polymeric nanoparticles (SCPNs), single polymeric chains capable of folding into a nanoparticle, have gained much interest over the past decade. Sur-prisingly, the new advances in this rela-tively young field have, to the best of our knowledge, not yet been applied in combination with glycopolymers. Keeping in mind that glycopolymers are mainly soluble in water and primarily syn-thesized for biomedical applications ranging from imaging probes to synthetic vaccines and drug-delivery carriers, it should be clear that single-chain folding must be able to occur in water. Interactions that can be used include covalent linkages, metal coordina-tion, hydrogen bonds, ionic interactions, and hydrophobic interactions, as is common in nature’s protein folding.

Preparation of SCPNs can primarily be divided into two fundamentally syn-thetic strategies, as introduced by Barner-Kowollik et al.[97,98] These two approaches are on the one hand ‘selective point folding’ and on the other hand ‘repeat unit folding’ (Scheme 20). Selective point folding of macromolecules makes use of complemen-tary recognition units at predefined positions

Scheme 15. The triblock copolymer synthesized by sequential RAFT polymerization and its host–guest interaction with self-assembly behavior. Repro-duced with permission.[88] Copyright 2015, Royal Society of Chemistry.

Scheme 16. Illustration of the micellization of PDEAEMA-b-PMAGlc block copolymer in water and recognition with protein Con A. Reproduced with permission.[92] Copyright 2010, John Wiley & Sons, Ltd.




along the poly mer chain to achieve extremely well-defined nanoparticles. On the other hand, repeat unit folding offers a less-defined and chaotic collapse, although it should be noted that this approach is synthetically more accessible. In order to achieve folding as found in nature, selective point folding is preferred, especially for glycopolymer systems where individual distances in between saccharide units can have a great influ-ence on lectin-binding.

4.1. Selective Point Folding

As previously stated, selective point folding is the preferred approach for the preparation of well-defined glycopolymeric

structures. However, the field is still young and most contribu-tions have been conducted in non-competing solvents based on hydrogen bonding arrays. An interesting example of this selective point folding methodology was introduced by Barner-Kowollik using a combination of two orthogonal H-donors and acceptor units.[99] Through this approach based on the inter-action of thymine and diaminopyridine and the self-association of cyanuric acid and the Hamilton wedge, the authors achieved an 8-shaped macromolecule. Although very elegant, this approach was conducted in a non-competing solvent, which eliminates its use in water.

Approaches that can be combined with glycopolymers in aqueous environments are those based on metal–ligand inter-actions, host–guest interactions, and covalent linkages. An

Scheme 17. Synthesis of triblock copolymer and its self-assembly in methanol, followed by dialysis against aqueous solutions of different pH values. Reproduced with permission.[93] Copyright 2015, American Chemical Society.




important example of these host–guest interactions is the well-known association between adamantane and β-cyclodextrin. Barner-Kowollik and co-workers successfully employed this interaction for the prepara-tion of cyclic α-ω-functionalized poly(N,N-dimethylacrylamide).[40] Single-chain folding and dissociation were able to be monitored by DLS and nuclear Overhauser enhance-ment spectroscopy (NOESY). The same group further introduced metal–ligand complexation to achieve selective point folding.[100] Triphenylphosphine ligands were employed to afford single-chain metal complexes in the presence of Pd(II) ions at

Scheme 18. Schematic illustration of the preparation of bioactive polyelectrolyte nanogels from natural and synthetic sugar polymers. Reproduced with permission.[95] Copyright 2016, Royal Society of Chemistry.

Scheme 19. Synthesis of glycopolymer-coated nano-phthalocyanine. Reproduced with permission.[96] Copyright 2016, Royal Society of Chemistry.




high dilution. Although the experiments were performed in chloroform and dichloromethane, it still proves the relevance of metal-coordination as a synthetic platform.

4.2. Repeat Unit Folding

In contrast to the selective point folding approach, repeat unit folding has received significant interest with numerous contributions, with Pomposo et al. as one of the main con-tributors.[97,98,101] As mentioned before, single-chain folding of glycopolymers demands self-assembly in water in order to have significant applications. Many covalent links have been utilized to date for the formation of SCPNs via covalent bonds; these include thiol-ene and thiol-yne coupling,[102,103] Michael addi-tion,[104–106] amide formation,[107] tetrazine-norbornene reac-tion,[108] alkyne homocoupling,[109] tetrazole-ene ligation,[110] and disulphide linkages.[111] It is evident that the scope of cova-lent linkages is broad and that many other contributions are expected in the following years.

Furthermore, the dynamic nature of supramolecular interac-tions can be useful for reversible and responsive glycopolymer synthesis. The most fascinating contributions in this field are undoubtedly from the group of E.W. Meijer and A. Palmans. The use of self-recognizing motifs such as the benzene-1,3,5-tricarboxamides (BTA) proved to be very beneficial for SCNP formation even in water, as is evidenced by many contributions (Scheme 21).[112–117] Upon reduction of temperature, BTA moi-eties self-assemble into helical aggregates, inducing a collapse into an SCPN. Evidently, every major supramolecular interac-tion that has a high association constant in water could be used. Many options are still to be explored.

Although not yet applied in glycopolymer science, single-chain folding technology based on both covalent and non-cova-lent interactions has received a significant increase of interest, as evidenced by myriad publications in recent years. In order to achieve specificity in lectin–glycopolymer binding, it is clear that selective point folding is preferred over repeat unit folding in glycopolymer design, and all of this in an aqueous environ-ment. Only the precise synthesis of not only the correct sugar moieties along the poly mer chain but also the precise collapse into a nanoparticle will provide efficient control. Self-assembly

into single-chain nanoparticles is found in nature on the scale of proteins and other biomacromolecules. It should thus be clear that further effort into the synthesis of these glyco-nanoparticles will most probably result in a gain in molecular understanding of lectin recognition events and be beneficial for future syntheses of glycopolymeric ligands.

5. Conclusion and Future Outlook

In comparison to glycopolymer self-assembly into glycopoly-meric micelles, worm-like micelles or polymersomes, both control over glycopolymer sequence and definitely control over glycopolymer single-chain folding, are in their infancy. In order to achieve effective and efficient lectin–glycopolymer binding, correct saccharide units have to be found at the cor-rect place and thus the correct position along the glycopolymer chain. This can only be achieved via the precise insertion of sugar units, and for this to occur, several techniques have been

Scheme 21. Collapse of an L-proline-containing, water-soluble polymer, based on the self-assembly of BTA moieties. Reproduced with permis-sion.[117] Copyright 2013, John Wiley & Sons, Ltd.

Scheme 20. Single-chain folding of well-defined synthetic polymers via repeat unit folding and selective point folding. Reproduced with permission.[98] Copyright 2016, John Wiley & Sons, Ltd.




explored, ranging from solid-phase glycopolymer synthesis to chain-growth polymerizations. Chain growth polymerizations provide sequence-control either by a difference in monomer reactivity or by sequential addition of glycomonomers. Solid-phase glycopolymer synthesis delivers perfect monodisperse glycopolymers and could be preferred from a biological point of view, despite the synthesis usually being limited to few oli-gomers. Synthesis via chain extensions, on the other hand, comes with greater dispersities but provides the possibility of a well-controlled synthesis on a bigger scale. In the future it is expected that single-chain folding of glycopolymers will gain significant interest, as this will give an extra dimension of architectural control, which has not been established to date in glycopolymer science. Furthermore, even smaller and more complex structures are expected to be synthesized such as sac-charide-containing molecular knots.[118] These structures will take more synthetic effort, but it is expected that these newly developed structures will have an increased spatial organiza-tion of the saccharide units, which will undoubtedly result in an increased lectin binding affinity.

AcknowledgementsWe would like to thank the European Commission Horizon2020 programme (EU-ITN EuroSequences Proposal no. 642083) for funding. C.R.B. and G.Y. also acknowledge EPSRC (EP/P009018/1) for the financial support.

Received: April 5, 2017Revised: May 21, 2017

Published online:

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Sequence and Architectural Control in Glycopolymer Synthesisbecergroup.sems.qmul.ac.uk/publications/papers/becer_085.pdf · containing macromolecules, are able to mimic structural