Progress in Polymer Science 117 (2021) 101393

Contents lists available at ScienceDirect

Progress in Polymer Science

journal homepage: www.elsevier.com/locate/progpolymsci

Strategies for the synthesis of sequence-controlled glycopolymers and

their potential for advanced applications
Théophile Pelras∗, Katja Loos∗
Macromolecular Chemistry and New Polymeric Materials, Zernike Institute for Advanced Materials, Faculty of Science and Engineering, University of
Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.

a r t i c l e i n f o a b s t r a c t

Article history: Natural and largely abundant macromolecules such as carbohydrates have become a center point of in-
Received 27 September 2020 terest for the polymer community, mostly due to their more environment-friendly nature and excellent
Revised 6 January 2021
capacity to bind to proteins found in the plant and animal reigns alike. The binding between saccha-
Accepted 7 April 2021
ride units and proteins is key to plethora of biological events, therefore a fundamental understanding of
Available online 15 April 2021
this mechanism could open doors towards a new age of biomedical advances. Synthetic macromolecules
Keywords: bearing saccharide units (i.e. glycopolymers) are of particular interest because they can be produced on
Block copolymers a controlled fashion with tailored molecular weight, structure, functionality and even sequencing. Vast
Nanostructures improvements have been made for the fabrication of sequence-controlled glycopolymers, thanks in part
Self-assembly to new monomer synthesis routes and to the recent developments in controlled polymerization tech-
Polysaccharides niques. This review article aims at providing the reader with a comprehensive guide on the synthesis of
Controlled polymerization
glycomonomers as well as on polymerization techniques for the production of block-type glycopolymers.
© 2021 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

1. Introduction

Few natural polymers are as ubiquitous and essential as car-

Abbreviations: AROP, anionic ring-opening polymerization; ATRP, atom
transfer radical polymerization; BCP, block copolymer; CDSA, crystallization-
driven self-assembly; CROP, cationic ring-opening polymerization; CTA, chain-
transfer agent; CuAAC, copper-catalyzed azide-alkyne cycloaddition; DEGA,
di(ethylene glycol) methyl ether acrylate; DEGMA, di(ethylene glycol) methyl
ether methacrylate; DMAEMA, 2-(dimethylamino)ethyl methacrylate; DMF,
N,N-dimethylformamide; FRP, free radical polymerization; HEA, 2-hydroxyethyl
acrylate; HEMA, 2-hydroxyethyl methacrylate; LAP, living anionic polymeriza-
tion; LCP, living cationic polymerization; MAA, methacrylic acid; nBA, n-butyl
acrylate; nBMA, n-butyl methacrylate; NCA, N-carboxyanhydride; NiPAAm, N-
isopropyl acrylamide; NMP, nitroxide-mediated polymerization; P3HT, poly(3-
hexylthiophene); PBLG, poly(benzyl-L-glutamate); PCL, poly(ε -caprolactone);
PDEGA, poly(di(ethylene glycol) methyl ether acrylate); PDEGMA, poly(di(ethylene
glycol) methyl ether methacrylate); pDNA, plasmid DNA; PEO, poly(ethylene oxide);
PHEA, poly(2-hydroxyethyl acrylate); PHEMA, poly(2-hydroxyethyl methacry-
late); PISA, polymerization-induced self-assembly; PLA, poly(lactic acid); PMAA,
poly(methacrylic acid); PMMA, poly(methyl methacrylate); PnBA, poly(n-butyl
acrylate); PnBMA, poly(n-butyl methacrylate); PS, polystyrene; RAFT, reversible
addition-fragmentation chain-transfer; ROMP, ring-opening metathesis polymeriza-
tion; ROP, ring-opening polymerization; rROP, radical ring-opening polymerization;
SET-LRP, single electron transfer ‘living’ radical polymerization; TEMPO, (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl).
∗
Corresponding author.
E-mail addresses: theophile.pelras@rug.nl (T. Pelras), k.u.loos@rug.nl (K. Loos).
bohydrates. In the plant and animal reigns alike, polysaccharides
play vital roles as energy source (e.g., starch and glycogen) [1] and
structural materials (e.g., cellulose [2], chitin [3] or collagen [4]).
Most importantly, carbohydrates are the cornerstone of plethora
biological events; for example, heparin is a key factor in blood co-
agulation, while hyaluronan is a crucial component of extracellular
matrix that participates in the inflammatory response and tissue
regeneration.
A vast array of complex biomolecular recognition events, such
as cancer metastasis, cell migration, microbial and viral infec-
tions or inflammatory response involve proteins found at the sur-
face of cells (generally named lectins) that possess the ability to
non-covalently, yet specifically, bind to carbohydrates. While most
monosaccharides weakly bind to their respective protein receptors,
carbohydrates display an enhanced activity that originates from
the multivalency of the many repeating units, a so-called “cluster
glycoside effect” [5].
Mimicking nature is an important goal in the development of
functional soft matter [6] and tremendous efforts have been made
to produce synthetic molecules with comparable cellular recogni-
tion ability. Whilst naturally occurring polysaccharides are highly

https://doi.org/10.1016/j.progpolymsci.2021.101393
0 079-670 0/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
T. Pelras and K. Loos
Fig. 1. General composition of a block-type glycopolymer.
abundant, their processing is often hampered by their limited solu-
bility and an inherent fragility. Glycopolymers, i.e. synthetic macro-
molecules with pendant sugar moieties (see Fig. 1), have thus been
developed as alternatives that are easier to process and which
characteristics can be fully tailored. These macromolecules can eas-
ily be achieved from the polymerization of glycomonomers, i.e. sac-
charide units with polymerisable groups. The vast range of reactive
functions (e.g., vinyl-based, strained olefin rings, lactones and lac-
tams or N-carboxyanhydride rings) and polymerization techniques
available have fueled the development of this new class of macro-
molecules. Alternatively, saccharide units with pendant functional
groups can be later attached to polymer chains possessing com-
plementary functions. In solution, these synthetic polysaccharides
feature an ability for recognition processes [7], similarly to their
naturally occurring analogues, but may as well be employed for
the hierarchical build-up of soft matter, another area we have long
tried to copy from nature.
The range of possibilities for self-assembled matter is, however,
limited when dealing with simple linear polymers, and such lim-
itation has rapidly stimulated the development of more complex
structures that can only be achieved through the precise assem-
bly of building blocks [8,9]. The emergence of robust and versa-
tile controlled polymerization techniques has enabled the forma-
tion of functional and sequence-controlled polymers, which prop-
erties such as overall molecular weight, weight fraction, sequenc-
ing and end-functionality can be precisely tailored. Changes in the
characteristics of block copolymers (BCP) affect the final morphol-
ogy of the self-assembled structures, which can then be shaped
into e.g., spheres, rod-like micelles, vesicles or more. The use of
block-type glycopolymers for self-assembly processes enables the
formation of saccharide-decorated nanoparticles, which bear po-
tential roles in biological events. Furthermore, the implementa-
tion of stimuli-responsive functions into the macromolecular de-
sign [10] enables the triggered collapse or shape-change of the
nanoparticles, opening doors towards saccharide-based drug deliv-
ery vehicles and adaptive materials.
This review article will discuss the various routes available for
the production of glycomonomers and sequence-controlled gly-
copolymers via ‘living’ polymerization techniques. Their ability
to self-assemble into well-defined nanostructures and their most
relevant applications in nanomedicine and nano-engineering will
be discussed. Note that we will differentiate polysaccharides (i.e.
macromolecules with their sugar units arranged along the back-
bone axis, see Fig. 1) and glycopolymers and will solely focus this
review on the later type, but can direct the reader to outstanding
reviews about block-type polysaccharides [11,12].
2
Progress in Polymer Science 117 (2021) 101393
Fig. 2. Synthesis routes for the formation of glycomonomers via ether linkage: (A)
silver triflate-catalyzed Königs-Knorr reaction [18], (B) Williamson reaction [21], (C)
BF3 -catalyzed [36] and (D) enzymatic [44] ether syntheses.
2. Synthesis of glycomonomers
Countless synthetic routes exist for the production of gly-
comonomers. Preference of a particular technique can be dictated
by parameters such as tolerance to functional groups, reagent types
or the need to avoid protection/deprotection steps. This section
will outline some of the most relevant routes reported.
2.1. Königs-Knorr reaction
The attachment of sugar moieties onto polymerizable functions
via Königs-Knorr reactions has been reported as early as the late-
60 with the attachment of N-carboxyanhydride (NCA) rings on
various saccharides [13,14]. More recently, glycomonomers bear-
ing acrylic polymerizable groups have similarly been produced
from protected sugar with a bromine group and 2-hydroxylethyl
methacrylate (see Fig. 2A) [15,16].
However, the highly toxic mercury catalyst that was employed
for the introduction of sugar moieties reaction is far from ideal, es-
pecially if any biological applications are foreseen. Safer reagents,
like for instance iodine [17], silver triflate [18] or silver carbon-
ate/silver perchlorate [19] have since been investigated to install
NCA ring precursors and vinyl functionalities alike.
2.2. Williamson reaction
The formation of an ether from an organohalide and a depro-
tonated alkoxide has been largely used for the production of gly-
comonomers. For instance, 2-chloroethyl vinyl ether has been re-
acted with an isopropylidene-protected glucose possessing a sin-
gle pendant hydroxy group in presence of potassium tert-butoxide
[20].
Hirao and coworkers have prepared a vast range of organosol-
uble styryl glycomonomers via Williamson reaction catalyzed by
sodium hydride. Cyclohexylidene- or isopropylidene-protected
monosaccharides were reacted with 3-(chloromethyl)styrene
to yield para- and meta-substituted monomers (see Fig. 2B)
[21,22]. In a later study, the synthesis of disubstituted gly-
comonomers by reaction of 3,5-bis(chloromethyl)styrene and
protected monosaccahrides was reported [23]. The same authors
also prepared plethora chloromethylbenzyl- and diphenylethylene-
substituted monosaccharides via the Williamson reaction between
isopropylidene-protected monosaccharide and excess of α ,α ’-
dichloro-p-xylene [24-27]. Alternatively, several chloromethyl
T. Pelras and K. Loos Progress in Polymer Science 117 (2021) 101393

phenylethylene derivatives were linked to protected monosaccha-

rides to yield unprecedented types of glycomonomers [24-28].
Maynard et al. have also produced various glycomonomers from
unprotected trehalose and 4-vinylbenzyl chloride, catalyzed by
sodium hydride. The reaction yielded the formation of four regioi-
somers (i.e. 2-O, 3-O, 4-O, and 6-O) with a higher substitution on
the 4-O position [29,30].
Acetyl-protected glucose [31,32], isopropylidene-protected glu-
cose [31-34] or decanoyl-protected cellobiose [31] bearing a sin-
gle bromine have been modified with excess of ethylene glycol
before reaction with 2-chloroethyl vinyl ether in presence of a
palladium catalyst. A similar protocol was followed using acetyl-
protected bromo glucosamine with a phtalimide moiety. Both ac-
etate and phtalimide protective groups were successfully removed
post-polymerization through a one-step procedure using hydrazine
monohydrate in a 1,4-dioxane/methanol mixture [35].

2.3. Other ether reactions

Fully protected monosaccharides, such as galactose pentaac-
etate, can undergo etherification reactions with an hydroxy vinyl
using boron trifluoride diethyl etherate as Lewis acid catalyst (see
Fig. 2C) [36]. Alternatively, methacrylic anhydride has been em-
ployed for the introduction of vinyl groups onto isopropylidene-
protected glucose in pyridine [37].
The use of good leaving groups such as tosyls facilitates the
formation of ether linkages between a polymerisable group and
a monosaccharide. Isopropylidene-protected galactose was reacted
with 4-toluenesulfonyl chloride before reaction with a hydroxy-
functionalized vinyl and catalyzed by tetra-n-butylammonium bro-
mide [38,39]. The use of a trichloroacetimidate leaving group on
acetyl-protected sugars before reaction with 4-vinylbenzyl alcohol
has also been reported [40]. Inversely, nitrophenyl leaving groups
can be installed in the hydroxy vinyls before coupling with unpro-
tected amino-sugar salts [41].
2.4. Enzymatic synthesis
More recently, the synthesis of glycomonomers through more
environment-friendly routes has been investigated. Enzymes, such
as ß-glucosidase, have been used for the production of anomer-
ically pure (meth)acrylic glycomonomers from D-glucose and
various hydroxyalkyl (meth)acrylates in mild conditions [42,43].
The transglycosylation between cellobiose or a p-nitrophenyl-
functionalized glucose and a hydroxyl(meth)acrylamide with the
same enzyme has also been published (see Fig. 2D) [44]. Li-
pases are also able to catalyze the formation of glycomonomers
from the reaction of methacrylic anhydride and the primary hy-
droxy group of complex glucose units [45,46]. Alternatively, the
transglycosylation reaction between potato starch and hydroxyalkyl
(meth)acrylates can be catalyzed by amylase [47], while cellulose
was used as glycosyl donor in combination with the synergic effect
of cellulase and ß-glucosidase [48]. These glycomonomers have
also been used as glycosyl acceptors to produce vinyl olligocel-
luloses, from either a combination of α -glucose 1-phosphate and
cellodextrin phosphorylase [49] or α -cyclodextrin and CGTase [50].
Other enzymes in their immobilized form, such as Novozyme 435,
have also been used to produce glycomonomers from simple sug-
ars and vinyl methacrylate [51].
2.5. Esterification via carbonyl chloride
Glycidyl-olefins have been synthesized through esterification
between unprotected amino-saccharides such as glucosamine and
(oxa)norbornenes with a carbonyl chloride moiety (see Fig. 3A)
[52]. Due to the higher reactivity of the primary amine, this
Fig. 3. Synthesis routes for the formation of glycomonomers via ester or amide
linkage: reaction of carbonyl chlorides onto (A) an amine [52] or (B) an alcohol
[55] and Steglich esterification between (C) an acid and an alcohol [58] or between
(D) an acid and an amine [61].
method permits the selective linkage of the two constituents via
an amide bond. Various protective groups (including acetate, ben-
zyl ether, triethylsilyl and trimethylphenyl) can be subsequently in-
troduced onto the glycomonomers to tailor their solubility in or-
ganic solvents [52]. Carbonyl chloride norbornenes were similarly
reacted with pendant hydroxy groups of various sugars but re-
quired all-but-one alcohols to be protected [53].
Acryloyl and methacryloyl chlorides have similarly been
used for the synthesis of vinyl-based glycomonomers, includ-
ing isopropylidene-protected fructose [54,55] (see Fig. 3B), glu-
cosamine hydrochloride [56,57] and acetyl-protected trehalose
[30].
2.6. Steglich esterification
The Steglich esterification between a vinyl acid and a monosac-
charide with all-but-one protected alcohols has been reported for
the production of organosoluble glycomonomers (see Fig. 3C) [58].
Alternatively, the Steglich esterification between an acid NCA
ring precursor and a monosaccharide with a pendant primary
amine has been used to link molecules via an amide function [59].
Inversely, a 4-vinylbenzylamine polymerisable group was installed
onto protected sugars possessing a single hydroxy group [60].
The higher reactivity of primary amines compared to that of al-
cohol groups can be taken advantage of for the Steglich esterifica-
tion without the requirement of protection steps. Kiessling et al.
have used this strategy to link unprotected mono- or bis-sulfated
galactose to (oxa)norbornenes with pendant acid functions (see
Fig. 3D). Due to poor yields, a pentafluorophenyl ester leaving
group was installed on the cyclic olefins and prove to be a more
efficient synthesis route [61].
2.7. Grignard reaction
Organometallic small molecules have also been employed
for the synthesis of glycomonomers. Wulff et al. have pre-
pared a vast range of styryl monomers from the reaction
between 4-vinylphenylmagnesium chloride and isopropylidene-
protected aldehyde monosaccharides, including D-mannitol, D-
gluconolactone, D-galactose and D-fructose (see Fig. 4A) [62,63].
Alternatively, a glucose monomer with barbituric acid linker was
produced on a similar fashion [64].

3
T. Pelras and K. Loos
Fig. 4. Synthesis routes for the formation of glycomonomers via coupling methods:
(A) Grignard reaction [63], (B) azide-alkyne [3+2] Huisgen cycloaddition [66] and
(C) lactone-amine coupling [71].
2.8. ‘Click’ reactions
Azide-alkyne [3+2] Huisgen cycloaddition (also known as
copper-catalyzed azide-alkyne cycloaddition, CuAAC) is another ef-
ficient method for the attachment of sugar groups onto polymer-
izable functions. An acetate-protected disaccharide with pending
alkyne group was reacted with azide-functionalized norbornene
featuring a Boc-protected guanine derivative to produce lactose-
guanine-functionalized cyclic olefins at high yield and in mild con-
ditions [65].
CuAAC reactions can also be performed in aqueous media,
through attachment of an azide-functionalized methacrylate to
mannose-alkyne and catalyzed by copper(II) sulfate and (+)-
sodium L-ascorbate in a methanol/water mixture and at room tem-
perature (see Fig. 4B) [66].
Thiol-ene reaction has also been used for the synthesis of gly-
comonomers, but the need of radical species for the coupling is
generally incompatible with vinyl functionalities. Thiolated NCAs
[67] and heterocyclic ring precursors [68] have been reacted with
acetyl-protected monosaccharides possessing a pendant allyl func-
tion to yield glycidyl heterocycles. Alternatively, thiolated-galactose
has been reacted in excess with a bis-methacrylate in presence
of dimethylphenylphosphine to yield a methacrylic glycomonomers
without the need of free-radical species [69].
2.9. Lactone-amine coupling
Mono- and oligosaccharide lactones can be readily produced
from their corresponding sugars and subsequently reacted with an
amino group to yield glycomonomers with an amide linker. This
route has been used by Kobayashi et al. as early as the mid 80
to produce lactose, maltose and maltotriose vinyl glycomonomers
by reaction of the corresponding lactones with p-vinylbenzylamine
[70]. This efficient synthesis route has later been used between
D-galactonolactose [71], D-gluconolactone [72] or D-lactonolactone
[72] and 2-aminoethyl methacrylate hydrochloride in methanol
and in presence of hydroquinone and triethylamine (see Fig. 4C).
2.10. Other chemistries
Many more synthetic routes have been followed to produce gly-
comonomers with peculiar linkages or functionalities. For instance,
the attachment of a NCA ring onto a monosaccharide via thio-urea
linkage has been reported [73], while p-vinylbenzylhydroxylamine
has been used to introduce an oxime linker between a disaccharide
and a styryl group [74].
Carbamate links were created through the reaction between
acetyl-protected monosaccharide propargyl 1,2-orthoester and a
ε-Boc-protected NCA ring precursor [75]. The reaction between
4
Progress in Polymer Science 117 (2021) 101393
D-glucosamine hydrochloride and hydroxyethyl acrylate [76], hy-
droxyethyl methacrylate [41] or poly(ethylene glycol) methacrylate
[77] to produce (meth)acrylic glycomonomers is further facilitated
by the introduction of a p-nitrophenyl leaving group. Alternatively,
the nitrophenyl-modified methacrylate could be used for the link-
age with tertiary amine-modified lactonolactone and maltonolac-
tone [78].
Norbornenes-based glycomonomers with more peculiar olefin
structures have been synthesized. For instance, the reaction be-
tween norbornene imide and triethylsilyl-protected mannose bear-
ing a single pending hydroxy group has been reported [79]. Alter-
natively, oxanorbornene anhydrides underwent a Mukaiyama ester-
ification with triethylsilyl-protected glucose and mannose to pro-
duce single [80] and double-functionalized cyclic olefins [80].
3. Glycopolymers from controlled polymerization
Herein, we were able to organize the synthesis of block-type
glycopolymers into four families of polymerization techniques. The
following section and Table S1 (Supporting Information) will de-
scribe the various macromolecules that have been produced and
outline relevant features.
3.1. Living ionic polymerization
In spite of the remarkable advances in more user-friendly con-
trolled polymerization techniques, living anionic polymerization
(LAP) remains highly attractive for both an academic and industrial
point of view. Due to its inherent nature that prevents chain-chain
termination, LAP permits the synthesis of macromolecules with
precise control over their molecular weight (up to millions of Da)
and chain-end fidelity as well as offers unrivaled dispersity (often
below Ð = 1.05) [81]. A number of drawbacks, including the need
for aprotic solvents, the difficulty to polymerize monomers with
unprotected acid or electrophilic functionalities, as well as the sen-
sitivity of the technique to oxygen and impurities have stimulated
the use of alternative techniques. While living cationic polymeriza-
tion (LCP) possess similar characteristics in terms of performances,
it also bears the disadvantage to be more prone to side-reactions.
Nevertheless, numerous strategies have been developed to permit
the controlled polymerization of functional monomers [82], no-
tably through the installation of protective groups (see Fig. 5).
Hirao et al. have produced a number of amphiphilic block
copolymers through sequential LAP of mono- [21,22] or bis-
functional [23] glycomonomers with styrene and removal of the
protective groups (see Fig. 6A). Alternatively, the authors have used
glucose- and galactose-substituted diphenylethylenes with either
mono- or bis-functional initiating systems to create glycidyl end-
or mid-functionalized polyisoprene [24], poly(methyl methacry-
late) (PMMA) [28] and polystyrene (PS) [24-27].
While styryl monomer are commonly used in LAP, acrylates and
methacrylate remains highly efficient as well. For instance, sequen-
tial polymerization of an isopropylidene-protected methacrylic gly-
comonomer and 1,1-dihydroperfluorooctyl methacrylate produced,
after deprotection, BCPs with a strong CO2 -amphiphilic character
able to form micelles with mean diameter of 27 nm in supercriti-
cal CO2 [37].
A large variety of narrowly dispersed macromolecules have
also been produced by Minoda and coworkers from the sequen-
tial LCP of vinyl ether-functionalized glycomonomers and isobutyl
vinyl ether (see Fig. 6B) [31-35]. Thin film deposition of the am-
phiphilic BCPs induced microphase separation into spheres, cylin-
ders or lamellae depending on BCPs composition and molecular
weight [31,33].
An interesting route combining both LAP and LCP has been
reported by Deffieux et al. for the synthesis of block-type gly-
T. Pelras and K. Loos
Fig. 5. Protective groups commonly introduced onto saccharides to prevent side-reactions and/or tailor their solubility: (A) isopropylidene, (B) cyclohexylidene, (C) acetyl,
(D) benzyl, (E) triethylsilyl and (F) triphenylsilyl-protected fructose.
Fig. 6. Strategies for the synthesis of block-type glycopolymers via (A) living anionic polymerization, (B) living cationic polymerization and (C) sequential living anionic and
cationic polymerizations. (D) Examples of amphiphilic block-type glycopolymers are depicted.
copolymers [20]. The authors first polymerized a PS block by
LAP, followed by functional termination with a chloroacetal group
and derivatization into α -iodo ether macroinitiator. This was later
used for the LCP of a protected glucose vinyl ether to produce
macromolecules with unprecedented composition (see Fig. 6C).
Amphiphilic BCPs were obtained after removal of the acetal
protective groups and their solubility in various solvents was
studied.
3.2. Ring-opening metathesis polymerization
Ring-opening metathesis polymerization (ROMP) of strained
cyclic olefins [83] (e.g., norbornene derivatives) is a straightfor-
ward and versatile technique for the one-pot production of well-
defined polymers. The large range of catalysts available (mostly
ruthenium carbene complexes [52], although palladium(II) chlo-
ride [84] and molybdenum complexes [53] have also been re-
ported) permits the polymerization of a wide range of monomers,
including those with unprotected hydroxy groups as well as sul-
fated functionalities that can be difficult to mask. Unfortunately,
very few studies have reported the formation of block-type gly-
copolymers via ROMP. This may be attributed to traces of tran-
sition metals that can be difficult to fully remove from the final
product, possibly hampering its use in biomedical applications, al-
though metal-free ROMP techniques have made a tremendous leap
forward [85].
Grubbs and coworkers have reported the first use of ROMP
to produce glycopolymers from unprotected glucose-norbornene in
water-in-oil emulsions using a ruthenium complex catalyst. Alter-
natively, protected glycomonomers could be copolymerized with
unfunctionalized norbornenes to yield both statistical and block-
type macromolecules (see Fig. 7A) [52].
The sequential ROMP of isopropylidene-protected gly-
comonomers in organic solvents and catalyzed by a molybdenum
alkylidene complex (i.e. Schrock catalyst) was used to produce
challenging yet well-defined sequence-controlled macromolecules,
including diblock, triblock as well as tetrablock copolymers [53].
3.3. Ring-opening polymerization
N-carboxyanhydride rings are commonly used for the precise
synthesis of polypeptides via ring-opening polymerization (ROP)
5
Progress in Polymer Science 117 (2021) 101393
[86,87] and a variety of functional groups can easily be attached
onto open ring precursors [88]. The anionic ring-opening poly-
merization (AROP) of NCA rings is capable of producing well-
defined polypeptides while being reasonably tolerant to side-
functionalities.
Okada et al. have employed this technique for the production of
many glycopolypeptides. While the use of a tertiary amine initiator
led to a so-called “activated monomer mechanism”, primary amine
systems led to AROP with a chain growth occurring at the amino
end group [89]. Amphiphilic BCPs were achieved from the one-pot
sequential AROP of acetal-protected glycomonomers and alanine-
NCA and subsequent deprotection (see Fig. 8A) [89]. Alterna-
tively, block-type glycopolymers were achieved through AROP us-
ing an amino-terminated polyoxazoline macroinitiator [90]. ‘Sugar
balls’ [91] (i.e. sugar-coated dendrimers) were also produced using
amino-terminated dendrimers to initiate the AROP of glucose and
amino-glucose NCA rings and grow short glycopolypeptide chains
[92].
The same authors have reported an interesting combination of
AROP and cationic ring-opening polymerization (CROP) to produce
block-type glycopolypeptides via mutual termination of two poly-
mer chains (see Fig. 8B). First an acetyl-protected glycopolypeptide
was produced via AROP of NCA heterocycles. Then, a polyoxazo-
line was synthesized by CROP and while still in a ‘living’ state, the
amine-terminated glycopolypeptide was introduced into the reac-
tion vessel to induce chain termination/coupling. The later removal
of the acetate protecting groups yielded amphiphilic BCPs with un-
precedented composition [93].
Gupta et al. have sequentially polymerized p-methoxybenzyl-L-
glutamate and glyco-NCA featuring a carbamate linkage via AROP,
initiated by a proton sponge alongside an aliphatic amine or a
short amine-functionalized poly(ethylene oxide) (PEO) to produce
diblock and triblock copolymers respectively [75]. The same type of
glycomonomer has been initiated by a PEO-NH2 and modified via
CuAAC to produce a PEO-block-glycopolypeptide with a hydropho-
bic dendrimer terminus [94].
Instead of primary amines, transition metals (e.g., cobalt [95],
iron [95] or nickel [96]) have been reported to initiate the ROP
of NCA heterocycles (see Fig. 8C). This technique was used to se-
quentially polymerize glyco-NCA with another hydrophobic hete-
rocyclic monomer to yield, after removal of the protective groups,
T. Pelras and K. Loos Progress in Polymer Science 117 (2021) 101393

Fig. 7. (A) Strategy for the synthesis of block-type glycopolymers via ring-opening metathesis polymerization. (B) Examples of amphiphilic block-type glycopolymers are
depicted.

Fig. 8. Strategies for the synthesis of block-type glycopolypeptides via (A) anionic ring-opening polymerization, (B) cationic ring-opening polymerization/chain-end polypep-
tide coupling and (C) transition metal catalyzed-ring-opening polymerization of NCA rings. (D) Examples of amphiphilic block-type glycopolymers are depicted.

amphiphilic BCPs able to self-assemble into well-defined nanos-

tructures [97].

3.4. Radical polymerization techniques

Radical polymerization techniques have been the subject of

tremendous improvements since their early stages and an incred-
ibly vast range of monomers, including those with unprotected
electrophilic groups, can nowadays be polymerized with little to
no side-reactions.

3.4.1. Free radical polymerization

Free radical polymerization (FRP) permits the synthesis of a
wide range of homopolymers and statistical copolymers with a
low overall cost, due to the absence of expensive deactivators
or catalysts. Its well-established experimental methods, ease to
scale up and relative tolerance to impurities also make it rele-
vant for industrial applications. The synthesis of glycopolymers by
means of non-mediated radical initiation has been reported as
early as in the mid-70 , when Kocourek et al. produced a vari-
ety of polyacrylamide-co-glycopolymers from unprotected vinylic
monosaccharides such as glucose [98], galactose [98-100], fucose
[98-100], mannose [98-100] as well as lactose [98]. However, FRP
does not permit the precise control of the macromolecules’ disper-
sity, molecular weight or chain-end functionality and prevents the
formation of sequence-controlled polymers. To overcome this limi-
tation, Kitano et al. have used a liphophilic C18 azobis(cyanovaleric
acid) to initiate the radical polymerization of unprotected man-
nose methacrylate in methanol and produce amphiphilic lipo-
glycopolymers (see Fig. 9A). In spite of a short hydrophobic seg-
ment, these pseudo-BCPs were able to self-assemble into lipo-
somes [101].
Alternatively, the production of block-type glycopolymers via
FRP could be achieved via post-polymerization chain-chain cou-
pling, but to the best of our knowledge, this has not yet been re-
ported.
Fig. 9. (A) Strategy used for the synthesis of pseudo-block-type glycopolymers via
free radical polymerization using an alkyl peroxide or azo initiator. (B) Example of
amphiphilic pseudo-block-type glycopolymer.
3.4.2. Atom transfer radical polymerization
Unlike FRP, atom transfer radical polymerization (ATRP) main-
tains good control over the macromolecules’ dispersity and chain-
end functionality. While the technique requires the incorporation
of several additives (i.e. initiator, copper catalyst and often deacti-
vator and ligand), their widespread availability, low price tag and
the high number of monomers that can be polymerized have en-
couraged its development [102], including for the production of
glycopolymers. Like for ROMP, traces of copper in the final product
may limit the use of the polymer for biological applications and
extensive purification may be required, although ATRP techniques
using lower amounts of copper and even metal-free alternatives
have been developed [103].
Li et al. have reported the sequential ATRP of styrene and
an acrylic glycomonomer for the formation of several PS-block-
glycopolymer amphiphilic BCPs. These macromolecules under-
went spontaneous self-assembly into spherical [16,104,105] and

6
T. Pelras and K. Loos
Fig. 10. Strategies for the synthesis of block-type glycopolymers via atom transfer radical polymerization, including (A) use of a bis-functional ATRP initiator, (B) modification
of polymer chain-ends with an acid bromide and (C) modification of ATRP-made glycopolymer chain-ends to perform another type of polymerization technique. (D) Examples
of amphiphilic diblock and triblock glycopolymers are depicted.
worm-like micelles [16,104-106], vesicles [15,104-107] and spheres
[104,105,107] depending on parameters such as the polymer com-
position, concentration as well as the presence of additives. Fukuda
et al. have used a similar route but performed the sequential poly-
merization in one-pot fashion, which lowers the number of steps
and facilitates the formation of copolymers [108].
Mono- and bis-functional ATRP initiators were employed by
Fernández-García and coworkers to produce a wide range of
amphiphilic diblock and terblock glycopolymers (see Fig. 10A).
Polymerization of unprotected glucose (meth)acrylate and
chain-extension with either n-butyl acrylate (nBA) [41] or
n-butyl methacrylate (nBMA) [109] has been carried out in
N,N-dimethylformamide (DMF). A similar strategy but with the
formation of the hydrophobic block first has been reported,
with the production of poly(n-butyl acrylate) (PnBA) [110,111]
and PMMA [111] macroinitiators and later chain-extension
with glycomonomers. Finally, chain extension of a poly(n-butyl
methacrylate) (PnBMA) macroinitiator by glycomonomer and 2-
(dimethylamino)ethyl methacrylate (DMEAMA) produced diblocks
with a mixed hydrophilic segment [112,113], while sequential ATRP
of all three monomers produced a sequence-controlled terblock
copolymer [113].
Many more vinylic monomers have been sequentially polymer-
ized with monosaccharide (meth)acrylates. For instance, the chain-
extension of a poly(2-hydroxyethyl methacrylate) (PHEMA) with
unprotected glucosamine methacrylate has been reported. Despite
a short water-soluble PHEMA segment, the double-hydrophilic
BCPs were able to self-assemble into well-defined nanoparti-
cles [114]. Similarly, Alexander et al. have reported the produc-
tion of glycopolymer-block-poly(di(ethylene glycol) methyl ether
methacrylate) (PDEGMA) through sequential ATRP. The thermo-
responsive character of the PDEGMA segment enabled the macro-
molecules to remain unimers below 15 °C and to assembled
into vesicles at higher temperatures. The mean nanostructures
size could also be reversibly tailored between 300 nm at 20 °C
and 500 nm at 37 °C [115]. Alternatively, Das et al. have re-
ported the synthesis of both poly(pyrenylmethyl methacrylate)-
block-glycopolymer [58] and poly(spiropyran methacrylate)-block-
7
Progress in Polymer Science 117 (2021) 101393
glycopolymer [116] via sequential ATRP. After removal of the iso-
propylidene protective groups, the BCPs featured an amphiphilic
character that could be suppressed through either cleavage of the
pyrenyl moieties via irradiation at 340 nm [58] or reversible iso-
merization of the spiropyran group at 360/560 nm [116].
Macromolecules, especially those with hydroxy end-groups,
can easily be transformed into ATRP macroinitiators by intro-
duction of bromine functionalities (see Fig. 10B). A vast range
of BCPs were achieved by polymerization of a glycomonomer
using PEO [117-120] or poly(propylene oxide) [118,119] ATRP
macroinitiators in chlorobenzene, N-methyl-2-pyrrolidinone, wa-
ter or water/methanol mixtures. Complex block compositions, in-
cluding coumarin-derivatized methacrylate, DMAEMA and glycol-
based methacrylate, have also been achieved from a PEO-Br
macroinitiator [121]. Triblock copolymers were also produced via
either sequential polymerization of the glycomonomer and an-
other methacrylate from PEO-Br [118] or using a bis-functional
poly(ε -caprolactone) (PCL) [118] or α -cyclodextrin-caged PCL ATRP
macroinitiators [122]. Shi et al. have cleverly modified both end-
groups of a PCL to allow chain-extension with a methacrylic gly-
comonomers, before cleaving the disulfide middle point to produce
thiol-functionalized diblocks able to attach onto gold nanoparti-
cles [123]. Other types of PCL-based ATRP macroinitiators such as
pyrene end-labeled [124], star-like [125] and nanoparticle-grafted
multibranched [126] have also been used for the polymerization
of glycomonomers. Interestingly, 4-arm block-type glycopolymers
have been achieved from either ROP of ε -caprolactone [127] or
AROP of hydrophobic NCA rings [128], followed by the introduction
of ATRP initiating sites and chain-extension with a methacrylic gly-
comonomers. More peculiar macromolecules, such as polypeptides,
can be modified to bear ATRP initiating sites for the polymeriza-
tion of glycomonomers. Maynard et al. have for instance modified
insulin and grown trehalose-based glycopolymer to yield a pep-
tide/glycopolymer hybrid [129].
Plethora ATRP initiators with end-groups able to remain un-
touched during polymerization can be synthesized and used for
the production of end-functionalized glycopolymers. For instance,
an alkyne-terminated ATRP initiator has been used by Müller et al.
T. Pelras and K. Loos
to produce glycopolymers of various lengths that were later at-
tached onto spider silk protein eADF4(C16) films via CuAAC [130].
Alkyne functions were also introduced post-ATRP via reaction with
excess of a bis-alkyne reagent and the modified glycopolymer was
subsequently attached onto azide-modified model protein scaf-
fold to yield virus-shaped nanostructures [131]. Alternatively, the
end-groups of ATRP-made polymer chains can be modified to
later conduct another type of polymerization technique, such as
ROP of alanine-NCA from a bis-amino-terminated glycopolymer
(see Fig. 10C). The resulting terblock copolymers were able to
self-assemble into spherical nanoparticles in aqueous media after
deacetylation of the sugar units [132-134].
Single electron transfer ‘living’ radical polymerization (SET-LRP)
(also known as Cu(0)-mediated radical polymerization), originally
introduced by Persec et al. [135,136], permits ultrafast polymeriza-
tion at room temperature while keeping excellent control over the
macromolecules’ dispersity and very high end-group fidelity [137].
SET-LRP has since become increasingly popular but few exam-
ples of glycomonomers have been polymerized with this method.
Haddleton and coworkers have reported the sequential one-pot
SET-LRP of mannose acrylate and di(ethylene glycol) methyl ether
acrylate (DEGA) in aqueous media, yielding block copolymers af-
ter nearly quantitative conversion [138]. The same authors have
also reported the impressive synthesis of PDEGA-glycopolymer and
poly(mannose acrylate)-poly(glucose acrylate) hexablocks, reaching
almost complete monomer conversion under a few hours [139].
3.4.3. Reversible addition-fragmentation chain-transfer
polymerization
Unlike its copper-mediated competitor, reversible addition-
fragmentation chain-transfer (RAFT) polymerization does not re-
quire the use of a metal catalyst, but in-lieu employs a chain-
transfer agent (CTA) that is able to reversibly cap growing poly-
mer chains. RAFT permits the polymerization of an incredibly vast
range of monomers [140,141] and the absence of metal residues in
the final product also makes it highly relevant if biological appli-
cations are foreseen.
A number of vinyl monomers have been polymerized from
macro-CTA bearing monosaccharide functionalities. For in-
stance, a poly(glucose methacrylamide) was chain-extended
with methacrylic acid to yield water-soluble BCPs with one
charged segment able to complex opposite-charged nanoparticles
[56]. Alternatively, an acetyl-protected glycopolymer has been pro-
duced using mono- and bis-functional CTAs and chain-extended
with nBA to respectively produce diblock and triblock glycopoly-
mers with narrow dispersity. A reverse synthesis, which relied
on the sequential polymerization of nBA and glycomonomer,
has also been reported [142]. An acetate-protected glucose has
been involved in the synthesis of triblock copolymers featuring
PnBA and poly(4-vinyl pyridine) segments. After deactylation,
the amphiphilic copolymers were able to self-organize into
patchy micelles before further assembly into larger aggregates
[143]. Sequential RAFT polymerization of a glycomonomer and
an azobenzene methacrylate yielded amphiphilic BCPs with a
light-sensitive segment that could be cleaved to modify the overall
solubility of the macromolecules and trigger the deconstruction
of the self-assembled structures [36]. Several reports featured the
chain-extension of methacrylic [142,144] or methacrylamide-based
[145] glycopolymers with N-isopropyl acrylamide (NiPAAm) in
DMF or water/dimethylsulfoxide mixtures or even more peculiar
uridine-based methacrylate [146] or 4-(pyrenyl)butyl methacrylate
[147]. Stenzel et al. have reported the use of water-insoluble 3-arm
CTA for the growth of short poly(2-hydroxyethyl acrylate) (PHEA)
chains via the Z-group approach before chain-extension with un-
protected glycomonomer in water/ethanol [231]. The same group
has also synthesized several glycopolymer-block-PMMA by chain-
8
Progress in Polymer Science 117 (2021) 101393
extension of a fructose-based macro-RAFT agent. Self-assembly
into micelles [148] or large vesicles [149] was successful after
removal of the isopropylidene groups. Another study demonstrated
the tremendous effect of drug loading on the final shape of the
nanostructures, ranging from rod-like micelles to large vesicles
[150]. The high chain-end fidelity offered by RAFT has also permit-
ted the fabrication of well-defined glycopolymer-containing ABC
triblock terpolymers with dispersities below Đ = 1.3 [151,152].
Alternatively, chain-extension of an unprotected water-soluble
glycopolymer-CTA with hydrophobic monomers, such as glycidyl
methacrylate [153] or 2-hydroxypropyl methacrylate [69] has
also permitted the production of amphiphilic glyco-BCPs via
polymerization-induced self-assembly (PISA) into a vast array of
nanostructures.
Other publications have reported the formation of a macro-
RAFT agent and later chain-extension with glycomonomers (see
Fig. 11A). For example, PS-based macro-CTAs have been chain-
extended with mannose [154] or lactose-based [155] styryl gly-
comonomers to produce, after deprotection, a series of am-
phiphiles able to assemble into vesicles. Narain and cowork-
ers have produced a vast range of block copolymers by se-
quential RAFT polymerization of 2-aminoethyl or 2-aminopropyl
methacrylamide and chain-extension with a methacrylamide gly-
comonomers [71,156-160]. A reverse polymerization sequence, first
producing a glycopolymer-CTA followed by chain-extension with
various comonomers has also been investigated [72,159,160]. In a
recent publication, our group has reported the formation of am-
phiphilic and double-hydrophilic block-type glycopolymers by the
respective chain-extension of PHEMA or poly(ethyl methacrylate)
with an enzymatically-produced unprotected glucose methacry-
late. Both amphiphilic and double-hydrophilic BCPs exhibited self-
assembly behaviors into polymeric nanoparticles [161]. Another
study has reported the use of bis-functional RAFT agent for the
formation of a N-acryloylmorpholine macro-CTA and later chain-
extension with a glycomonomers to yield ABA triblock copolymers
[162].
Nanogels with various compositions have been produced by
sequential RAFT polymerization of various monomer blends.
Macro-CTAs were produced by either homopolymerization of
glycomonomers or copolymerization of glycomonomer and
methacrylic acid (MAA) or 2-aminoethyl methacrylamide. Then
chain-extension with small amounts of cross-linker as well as var-
ious combinations of glycomonomer/DEGMA or DEGMA/MAA was
performed [163-167] (see Fig. 11B). Alternatively, a poly(glucose
methacrylamide) was produced using a C12 chain-transfer agent
before stabilization in emulsions and chain-extension with styrene
and small amount of disulfide crosslinker. The nanoparticles un-
derwent reductive degradation into their linear components upon
treatment with 1,4-dithiothreitol [57].
Chain-transfer agents with hydroxyl end-functionalities have
been used for both the ROP of lactones and the RAFT polymer-
ization of a glycomonomer (see Fig. 11C). RAFT polymerization of
a glycomonomer, copolymerization of glycomonomer and HEA as
well as sequential polymerization were performed from a ROP-
made poly(lactic acid) (PLA) macro-CTA. The study demonstrated
the tremendous influence of the micellar shell composition onto
cellular uptake [168]. The use of chloroethyl acrylate instead of
HEA has also permitted the direct conjugation of drugs onto the
macromolecules [169]. Further chain-extension with low amounts
of diacrylate has also enabled the cross-linking of the micellar core
and the formation of stable sugar-decorated nanoparticles [170].
Alternatively, a PCL-trithiocarbonate was used to mediate the se-
quential polymerization of an isopropylidene-protected galactose
acrylate and DEGA before installation of near-infrared probes [171].
Another PCL macro-CTA was employed to copolymerize organosol-
uble fructose acrylate with a methylene dioxepane derivative via
T. Pelras and K. Loos Progress in Polymer Science 117 (2021) 101393

Fig. 11. Strategies for the synthesis of block-type glycopolymers via reversible addition-fragmentation chain-transfer polymerization, including (A) sequential RAFT polymer-
ization and deprotection of the glycosides, (B) formation of diblock copolymers with a cross-linked core, (C) use of a hetero bis-functional chain-transfer agent to conduct
two orthogonal polymerization techniques, (D) sequential utilization of ring-opening polymerization and RAFT/radical ring-opening polymerization and (E) surface-initiated
RAFT polymerization. (F) Examples of amphiphilic block-type glycopolymers are depicted.

RAFT-mediated radical ring-opening polymerization (rROP) (see
Fig. 11D). The resulting amphiphilic BCPs assembled into micellar
structures, which core can be biodegraded [54]. In a last study, a
4-arm PCL was modified to bear CTAs, which enabled RAFT poly-
merization of a methacrylic gluconolactone. The branched copoly-
mers were able to self-assemble into vesicles and to encapsulate
inorganic materials [172].
Liu et al. have produced several macromolecular architec-
tures from the modification of PHEMA-block-glycopolymer. The
esterification of the HEMA hydroxy groups with acryloyl chlo-
ride introduced vinyl functionalities without interfering with the
isopropylidene-protected glucose units. After removal of the pro-
tective groups, the vinyl functions underwent thiol-end coupling
with a thiolinated reduced glutathione to yield comb-like gly-
copolymer/peptide bioconjugates able to self-assemble into mi-
celles [173]. A similar PHEMA-block-glycopolymer was chain-
extended with NiPAAm to yield a terblock copolymer before use
of the HEMA units as initiating sites for the ROP of ε -caprolactone.
After deprotection, the terpolymer with comb-like middle segment
featured self-assembly behavior with a partially thermo-responsive
core [174]. Other macromolecules with controlled branching have
been produced from the chain-extension of a poly(methyl acrylate)
macro-RAFT agent with isopropylidene-protected galactose acrylate
and small amounts of an acrylic-CTA. The resulting amphiphilic
branched copolymers self-assembled into nanoparticles, which size
was inversely proportional to the polymer molecular weight. The
increase of monosaccharide density due to branching did not af-
fect the overall size or morphology of the nanoparticles [175].
Finally, although less popular than its ATRP equivalent [176],
surface-initiated RAFT has proven to be an efficient method for the
growth of glycopolymer chains from a surface (see Fig. 11E). Sten-
zel et al. have reported the attachment of a chain-transfer agent
onto a modified silicon wafer and sequential polymerization of
acrylamide glycomonomer and NiPAAm using the RAFT Z-group
approach [177]. To the best of our knowledge, this represent the
sole example of block-type glycopolymer grown from a surface.
3.4.4. Nitroxide-mediated polymerization
Nitroxide-mediated polymerization (NMP) is another type of re-
versible deactivation radical polymerization, which uses a nitroxide
radical as capping agent. NMP possess similar strengths compared
to RAFT, including a simplicity of usage and the absence of metal
residues in the final polymers, but also features a chemistry that
does not involve sulfur and permits the controlled polymerization

9
T. Pelras and K. Loos
Fig. 12. Strategies for the synthesis of block-type glycopolymers via nitroxide-mediated polymerization, including (A) sequential polymerization, (B) formation of a pseudo
block-type glycopolymer using an alkyl alkoxyamine initiator and (C) sequential polymerization through copolymerization of a protected glycomonomer and a vinyl
comonomer and later chain-extension with pure vinyl monomer. (D) Examples of amphiphilic block-type glycopolymers are depicted.
of dienes as well as an excellent control on styrene derivatives.
However, NMP suffers from a few drawbacks, including typically
slower kinetics that require higher temperature, poor control of
methacrylates due to side-reactions and lower commercial avail-
ability of nitroxides and alkoxyamines [178]. These have unfortu-
nately limited the number of reports using this technique, but a
few block-type glycopolymers have nonetheless been reported.
Since NMP offers unrivaled control over the dispersity of PS-
based macromolecules, most of the glycomonomers produced bear
a styryl polymerisable group. Wulff et al. have polymerized nu-
merous isopropylidene-protected glycomonomers using (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl) (TEMPO) as nitroxide initiator. The
macromolecules were later used as macroinitiators for the pro-
duction of glycopolymer-block-PS (see Fig. 12A) [62,63]. Inversely,
a PS macro-initiator has been used for chain extension with the
same glycomonomers [62]. The NMP of a glycomonomer using
a bis-functional alkoxyamine initiator and later chain extension
with styrene has permitted the production of triblock copolymers
with molecular weight as high as 26 kDa and dispersities below
Ð = 1.17.
Another study has reported the formation of nanoparticles with
a cross-linked glyco-core from the chain-extension of TEMPO-PS
with styryl glucose or maltohexaosyl and small amounts of divinyl-
benzene as cross-linker [179].
Pseudo block-type glycopolymers have also been achieved via
the NMP of glycomonomers using C18 aliphatic alkoxyamine ini-
tiators (see Fig. 12B) [180,181]. Some of the resulting amphiphilic
lipo-glycopolymers were reported to self-assemble into liposomes
after deacetylation of the saccharides [180].
While NMP typically involves styryl monomers, other vinyl
functionalities can also be polymerized individually [181,182]
or alongside a comonomer (see Fig. 12C) [183]. For in-
stance, a methacrylic glycomonomer has been copolymerized
with styrene to conduct in a controlled fashion before chain-
extension with styrene to create a (PS-co-glycopolymer)-block-
PS macromolecules able to assemble into micellar structures in
10
Progress in Polymer Science 117 (2021) 101393
aqueous media and into honeycomb films when cast onto a
substrate [183].
4. Glycopolymers from post-polymerization modification
Controlled polymerization techniques are efficient for the syn-
thesis of block-type glycopolymers, but several drawbacks may
arise from this strategy. The need to protect glycomonomers for
a use with less-tolerant techniques or to more easily copolymer-
ize them with hydrophobic monomers is a common obstacle. An-
other difficulty can arise in the complex multi-step synthesis of
glycomonomers that may require the use of large quantities of
dangerous or even toxic reagents; a downside that defeats the
purpose of these more ‘environment-friendly’ monomeric substi-
tutes. On the other hand, multiple methods to install functional
groups onto macromolecules post-polymerization have been im-
plemented [184]. However, these reactions may not always go
to completion due to steric hindrance, especially when involving
bulky attachments, which may result in the production of statisti-
cal copolymers instead. The development of highly efficient attach-
ment routes and the conversion of less reactive functional groups
into more reactive ones has nonetheless facilitated the production
of block-type glycopolymers. This section and Table S2 (Supporting
Information) will outline the various strategies available to do so
and report some of the most outstanding structures achieved.
4.1. Azide-alkyne cycloaddition
Amongst the many strategies available to attach saccharides
onto polymer backbones, the most employed one remains CuAAC,
mainly due to its high performances in mild conditions. Lecom-
mandoux et al. have produced a large range of block-type polypep-
tides through sequential AROP using a tertiary amine/LiBr initi-
ating system. Azide-functionalized galactose [185-187] and lactose
[187] were subsequently installed via CuAAC (see Fig. 13A). The re-
sulting amphiphilic glycopolypeptides successfully self-assembled
into polymersomes [185] or micellar structures [186,187].
T. Pelras and K. Loos
Fig. 13. Strategies for the post-polymerization installation of sugar units to yield diblock copolymers via (A) CuAAC, (B) thiol-ene reaction, (C) aminosaccharide attachment
and (D) end-to-end chain coupling. (E) Examples of amphiphilic block-type glycopolymers are depicted.
More complex architectures such as ‘tree-like’ and dendron-
terminated polymers have been produced with a similar strat-
egy. Poly(benzyl-L-glutamate)-block-poly(propargylglycine) copoly-
mers have been clicked with various azido-terminated polysac-
charides, including galactan [187], hyaluronan [188], as well as
dextran [188,189]. Alternatively, a poly(benzyl-L-glutamate) (PBLG)
was synthesized from an amino-azide initiator, leaving the azide
moiety untouched for later attachment of galactose dendrons [190].
Self-assembly of these branched architectures led to the formation
of large nanoparticles [187-190] and even lamellae [189]. Insertion
of alkyne functionalities has also been performed after sequen-
tial AROP of a Boc-protected aminopeptide for later use to attach
galactose or lactose units [191].
Other polymerization techniques have been used for the for-
mation of alkyne-containing BCPs. A PLA macro-CTA has been
chain-extended with trimethylsilyl-protected alkyne acrylate be-
fore removal of the protective groups and CuAAC to produce galac-
tose, mannose or lactose-based BCPs. The PLA segment under-
went crystallization-driven self-assembly (CDSA), yielding sugar-
decorated micelles, rods and platelets [192]. Alternatively, the
epoxy groups of a RAFT-made poly(glycidyl methacrylate-block-PS
were modified to bear alkyne functions before clicking various
monosaccharides [193].
In another report, a PEO macro-CTA has been stepwise chain-
extended with 4-vinylbenzyl chloride and styrene before replace-
ment of the chlorine atoms by azide functions. These were sub-
sequently used for cycloaddition using acetyl-protected galactose
alkyne to produce, after deprotection, ABC terblock copolymers
[194].
4.2. Thiol-ene reaction
Thiol-ene and thiol-yne reactions are similarly known to be effi-
cient for the post-polymerization modification of macromolecules
and the absence of metal residues make them more relevant for
the production of functional polymers for biological applications.
11
Progress in Polymer Science 117 (2021) 101393
The sulfide linkage is also more flexible [195] and may be more
adequate for optimal lectin recognition [196].
For instance, sequential RAFT polymerization of DEGMA and
HEMA and later introduction of allyl groups has permitted the
thiol-ene attachment of glucose-mercaptan. The block glycopoly-
mers reversibly self-assembled into micellar structures when the
solution temperature was set above the PDEGMA’s lower critical
solution temperature [197].
Radical polymerization techniques do not permit the well-
controlled synthesis of macromolecules with pendant allyl groups,
so other routes have been sought to avoid protection/deprotection
steps or further post-polymerization modifications. Schlaad et al.
performed sequential LAP of 1,2-butadiene and styrene [198] or
1,2-butadiene and ethylene oxide [199] and subsequent attachment
of glucose-mercaptan to respectively yield amphiphilic and double-
hydrophilic BCPs (see Fig. 13B), both of which were able to self-
assemble into vesicles. This strategy suffers from unavoidable side-
reactions, namely the anti-Markovnikov addition of mercaptan rad-
icals onto poly(1,2-butadiene), which leads to the formation of six-
member rings within the polymer chain and lowers the reaction
efficiency. Other polymerization techniques, such as the AROP of
heterocycles from a PEO-NH2 [200], or the sequential ROP of allyl
ethylene glycol and lactide [201] can circumvent this problem to
yield sequence-controlled block glycopolymers.
4.3. Other strategies
Other methods previously described for the production of gly-
comonomers have also been employed for the post-polymerization
attachment of monosaccharides. BCPs featuring PnBA and PHEA
[76] or PHEMA [202] segments have been functionalized with p-
nitrophenyl carbonate groups before attachment of galactosamine,
glucosamine or mannosamine to produce amphiphilic diblock
and terblock BCPs (see Fig. 13C). Another leaving group, namely
pentafluorophenyl, can be used for the facile modification of poly-
mer chains using amino-functionalized saccharide units [203].
T. Pelras and K. Loos
Alternatively, the reaction between gluconolactone or lactono-
lactone and an ammonium salt has been employed for the
post-polymerization modification of a poly(L-lysine)-block-
polytetrahydrofuran-block-poly(L-lysine). The resulting amphiphilic
terblock copolymer displayed self-assembling behavior into
nanoparticles [204].
Despite large potential for the post-polymerization modification
of epoxy-functionalized polymers, only one study has reported its
reaction with mercaptan-monosaccharide. Interestingly, the Cu(0)-
mediated poly(glycidyl acrylate)-block-poly(propargyl acrylate) was
able to be selectively modified via thiol-epoxy and CuAAC with
mercaptan and azide-functionalized sugars respectively [205].
While efficient on a small molecule size, Steglich esterifica-
tion is rarely employed for the post-polymerization modification of
macromolecules with saccharide units. Thus, few examples exist,
including the use of glucosamine hydrochloride and ROMP-made
polymer chains that featured small number of pendant acid groups
[206,207].
4.4. End-to-end coupling
While the end-to-end coupling has been extensively used for
attaching natural polysaccharides onto synthetic polymers [11,12],
a handful block-type glycopolymers have been produced as well,
see Table S3 (Supporting Information) for more details. Müller
et al. have produced an azido-terminated poly(3-hexylthiophene)
(P3HT) via Grignard metathesis polymerization and an alkyne-
terminated glycopolymer via ATRP before using CuAAC to link
both moieties and yield an amphiphilic BPC (see Fig. 13D). The
macromolecules were able to self-assemble into vesicles and pos-
sessed fluorescent properties originating from the conjugated P3HT
segment [208]. An alkyne-terminated glycopolypeptide was pro-
duced by AROP before coupling to azide-bis-PCL to produce mik-
toarm star polymers. Tailoring the blocks weight fractions en-
abled the selective production of micelles, nanorods and vesi-
cles in aqueous media [209]. In another study, PLA was pro-
duced from the organo-catalyzed ROP of lactide using 2-propyn-
1-ol as initiator, while a glycopolymer was prepared via ATRP us-
ing an azide-functionalized initiator. The coupling of the two seg-
ments via CuAAC led to the formation of amphiphilic block copoly-
mers able to form nanoparticles in aqueous media [210]. Alterna-
tively, a RAFT-made trisaccharide-based glycopolymer underwent
chain-end modification to feature an azide group that was later
clicked to an alkyne-modified protein [211]. Similarly, glucosamine
units were attached onto an azide-functionalized poly(acrylic acid)
through Steglich esterification before CuAAC with avidin or bovine
serum albumen [212].
A variety of natural polymers, such as tripeptide reduced glu-
tathione [213], have also been attached to synthetic glyco-based
macromolecules. The modification of the Z-group of chain-transfer
agents permits the introduction of disulfide aldrithiol functions,
which can later be reacted with a thiol-terminated natural polymer
chain to yield BCPs. The disulfide aldrithiol group has also been
directly incorporated into a chain-transfer agent [214] or an ATRP
initiator [215] and proved to be preserved during the polymer-
ization of a glycomonomer, before coupling with either thiolated
hen egg white lysozyme or thiolated siRNA. Alternatively, amine-
terminated insulin has been linked to a trehalose-based glycopoly-
mer via sodium cyanoborohydride-catalyzed reductive amination.
The polymer-drug conjugate displayed higher stability and greater
circulation time compared to the pristine insulin [216].
A succimide-terminated glycopolymer was produced either via
copper-mediated polymerization of a mannose glycomonomer or
via the post-polymerization attachment of mannose. Both poly-
mer underwent linkage to bovine serum albumin via succimide-
thiol chemistry to produce protein/polymer hybrids [217]. Finally,
12
Progress in Polymer Science 117 (2021) 101393
Kobayashi et al. synthesized an amino-terminated glycopolymer
via free-radical polymerization, before iodoacetylation and cou-
pling with a thiol-modified DNA strand. The coupling procedure
minimally affected the DNA conformation and its ability to conju-
gate to complementary strands [218].
5. Applications of block-type glycopolymers
The high number of saccharide units within glycopolymers
makes them ideal for the multivalent interaction with cells, en-
zymes and lectins. Therefore, glycopolymers and their block-
types analogues have been mainly used in biomedicine, although
plethora highly promising applications were reported.
5.1. Binding to lectins and enzymes
Macromolecules featuring saccharide units are often tested for
their ability to bind to a large range of lectins. For instance, sugar-
decorated nanoparticles built from PBLG-block-polygalactose dis-
played significantly higher binding activity with galectin compared
to free galactose in solution [187], while diblock and terblock
glycopolymers featuring glucosamine units demonstrated selective
binding for Concanavalin A lectin [76,202]. In addition to a binding
affinity to lectins, some glycopolymer systems have also demon-
strated an ability to scavenge radicals during a DPPH assay, giving
them potential as anti-oxidant therapeutics [213].
Controlled branching can further increase the multivalency of
glyco-BCPs. Lecommandoux et al. have employed some of their
tree-like block glycopolypeptides for interaction with enzymes. The
amphiphilic PBLG-block-polygalactose self-assembled into well-
defined nanoparticles with a saccharide shell. The particles were
then exposed to a variety of glucosidases, including α - and β -
Glcase, α - and β -Galase as well as α - and β -Manase, the inhibition
of which was measured. In particular, the nanoparticles were able
to significantly increase the inhibition potency towards Jack bean-
mannosidase compared to the free sugar analogue (see Fig. 14A)
[186].
Additional characteristics of the macromolecules can be tailored
to dictate or enhance the binding with proteins. The mannose-
containing multiblock glycopolymers produced by Haddleton and
coworkers have been used for the binding to DC-SIGN, a lectin
typically found on macrophages and dendritic cells that binds to
micro-organisms. While the precise sequencing of the polymers
did not enhance the binding affinity with DC-SIGN, higher man-
nose content played a positive role in this biological event [139].
Du et al. have cleverly used the binding capability of lectins to
produce “sugar sponges” (i.e. vesicles able to swell while absorbing
free sugar molecules from the dispersion medium, see Fig. 14B),
which has potential as insulin and antidiabetic drug-free alterna-
tive for regulating glucose in the blood stream. The Concanavalin A
incorporated into the sugar sponge reversibly absorbs the glucose
from the dispersion, evidenced by a swelling of the nanoparticles
[121].
5.2. Interactions with micro-organisms
The high density of saccharide units surrounding glycopolymer-
based nanoparticles, mimicking cellular glycocalyx, provides
them with enhanced recognition with living organisms such as
macrophages. Both in vitro and in vivo experiments demon-
strated the higher response of PS-block-glycopolymer-based self-
assembled nanoparticles compared to their PEGylated analogues
[193]. Other studies have reported the enhanced ability of gly-
copolymer nanoparticles with thick and dense saccharide shell to
penetrate cell membranes [168] as well as to move faster into tu-
mor spheroids [169].
T. Pelras and K. Loos Progress in Polymer Science 117 (2021) 101393

Fig. 14. Interaction of glyco-based nanoparticles with lectins. (A) Polypeptide-based nanoparticles are able to inhibit Jack bean α -mannosidase activity. [186], Copyright 2012.
Reproduced with permission from the Royal Society of Chemistry. (B) Block-type glycopolymers self-assemble into “sugar sponges” and may act as new generation diabetic
drugs to regulate sugar concentration. Transmission electron microscopy images of a sugar sponge in (B1) low sugar and (B2) high sugar dispersion media. [121], Copyright
2017. Adapted with permission from the American Chemical Society.

Fig. 15. Interaction of glycosylated nanoparticles with micro-organisms. (A) The nature of the saccharide units – i.e., mannose (A1), galactose (A2) or lactose (A3) – can
dictate the particles morphology, which tailors their interaction with macrophages. [192], Copyright 2019. Adapted with permission from the American Chemistry Society.
(B) Polymerization-induced self-assembly of block-type glycopolymers and interaction with type 1 piliated E. coli to form bacteria clusters. Fluorescence microscopy images
of the polymer-induced bacteria clusters (B2) and (B3) compared to the negative control (B1). [153], Copyright 2019. Adapted with permission from Elsevier Science Ltd.

The size and shape of the nanoparticles can play an important
role in the expression of biological events. CDSA-made nanopar-
ticles ranging from spherical micelles to rods and platelets were
obtained from PLA-block-glycopolymer and exposed to RAW264.7
macrophages (see Fig. 15A). The authors demonstrated that
platelet-shaped nanoparticles induced higher inflammatory re-
sponse than cylindrical analogues, while smaller particles also im-
proved the immune-response [192].
Alexander et al. have used double hydrophilic glyco-BCPs
for the formation of vesicles that are able to bind to mu-
tant strains of E. Coli and form clusters of around 150 bac-
teria and 60–90 vesicles each. While addition of glucose en-
abled the dose-dependent breakdown of the cell-polymer ag-
gregates, interfacial interaction triggered the disruption of the
vesicular membranes [115]. Recognition of mutant E. Coli with
glycopolymer has also been achieved from mannose-decorated
cross-linked nanoparticles. While bacterial association was sim-
ilar between non-cross-linked and cross-liked particles, disul-
fide bonds permitted the triggered reduction by addition of 1,4-
dithiothreitol. This enabled selective release of cargo and easier re-
nal elimination through the production of low molecular weight
by-products [57].
Other micro-organisms have been targeted by glyco-BCPs. A
trisaccharide-containing polymer was conjugated to chicken serum
albumin and exposed to Candida albicans in order to test the poly-
mer immunogenic response. The study demonstrated that a more
robust response was produced by the glycopolymer conjugate than
trisaccharide-tetanus toxoid, a conventional antifungal drug [211].
Finally, the interaction between glycopolymer-decorated
nanoparticles and bacteria [153] can be taken advantage of in
biomedicine, for instance to trigger the formation of clusters (see
Fig. 15B). Antimicrobial activity of terblock glycopolymers with a
quaternized DMAEMA block or diblocks possessing a quaternized
DMAEMA/glycopolymer segment has been reported. The study
investigated the potency of the positive charges against bacte-
ria while trying to limit toxicity towards white blood cells. In
vitro experiments proved that the block-statistical glycopolymers
were slightly less effective against bacteria and fungi strains but
most-importantly far less toxic for the blood cells [112].
5.3. Delivery of therapeutics
Drug delivery is one of the most common usage of self-
assembled nanoparticles [219], as the polymeric structures protects

13
T. Pelras and K. Loos
Fig. 16. Utilization of glycopolymer-based particles for the delivery of active substances. (A) The drug loading content into self-assembled soft nanoparticles influences
its overall shape – ranging from rods (A1) to large (A2) and small vesicles (A3) – and outer shell hydration. [150], Copyright 2018. Adapted with permission from the
American Chemical Society. (B) Diverse functionalities, such as degradability by enzymes, can be integrated into the macromolecular design to facilitate drug delivery or renal
elimination. (B1) Transmission electron microscopy image of the pristine glycopolymer nanoparticles and (B2) dynamic light scattering measurements of the nanoparticles
before and after enzymatic degradation. [54], Copyright 201. Adapted with permission from the American Chemical Society.
the cargo against degradation and renal elimination, reduce its tox-
icity and enables its delivery in a controlled manner. The enhanced
recognition of glycosylated nanoparticles compared to other ana-
logues has further stimulated their used for the delivery of vari-
ous therapeutics. More advanced systems may even carry two sub-
stances of interest, for example a drug and imaging agent that per-
mits the monitoring of cellular death [151].
Drug loading is one of the key steps in the fabrication of
nanomedicines and was shown to be far from trivial. Different pro-
tocols of paclitaxel loading into glycopolymer micelles affect the
amount of drug loaded as well as the overall shape of the par-
ticles. These two factors have large impacts on the biological ac-
tivity and it is therefore essential to fully understand this pro-
cess [148]. The amount of drug that is incorporated into polymer
particles also stimulates changes in size [204] as well as overall
morphology. As such, PMMA-block-poly(fructose methacrylate) as-
sembled into cylindrical micelles in absence of drugs, while the
addition of small amount of cargo led to the formation of poly-
mersomes, the size of which decreased with increasing amount
of drug. This effect was correlated to a reduced water content in
the glycopolymer shell and significant decrease in cellular uptake
(see Fig. 16A) [150]. Alternatively, the drugs themselves can un-
dergo transformation once incorporated into self-assembled struc-
tures. A dual drug system composed of curcumin and ellipticine
was loaded into vesicles based on the same BCP and showed to
recrystallize into a different polymorph inside the polymer vehicle
[149]. Studies have also suggested an effect of the macromolecu-
lar structure on the ability to load and release drugs. For example,
4-arm polymers with a hydrophobic PBLG core stabilized by gly-
copolymer termini displayed higher doxorubicin (i.e. hydrophobic
anticancer drug) loading efficiency than linear analogues [128].
Another key process in the use of drug delivery nanocarriers
is the escape of the therapeutics from the polymer particles.
Kinetic studies of the release of doxorubicin from terblock
polysaccharide-block-polytetrahudrofuran-block-polysaccharide at
pH = 5.0 demonstrates a rapid release within the first 2 hours and
slower rate thereafter, attributed to the diffusion of the drugs from
the particles to the medium [204]. Additional features such as
stimuli-responsiveness can be implemented in the macromolecular
design to aid the release of therapeutics. For instance, azobenzene
groups can undergo isomerization from their stable trans form to
the more polar cis one within minutes under UV irradiation, before
returning to their original state in the dark. Galactose-decorated
micelles with a poly(azobenzene methacrylate) core have been
produced and displayed similar behavior, which may aid the
expulsion of the payload [36]. Thermo-responsiveness has also
been introduced in galactose-decorated nanogels, which cross-
14
Progress in Polymer Science 117 (2021) 101393
linked PDEGMA core changes solubility to expel iodoazomycin
arabinofuranoside, a clinical imaging drug [166].
While therapeutics can be loaded into self-assembled struc-
tures, the covalent linkage of the payload to the macromolecules is
another viable option. This ensures quantitative incorporation into
the nanoparticles and can prevent premature release due to the
breakdown of the aggregates. This strategy, particularly used for
the attachment of imaging agents, has been reported by Yan et al.
for the fabrication of PCL-block-PDEGA-block-poly(galactose acry-
late) featuring near-infrared probes at the termini of the polyester
segment. Cell studies revealed fast endocytosis into HepG2 lines, a
process that could be monitored via fluorescence microscopy using
the probe [171]. Alternatively, the substance of interest – often a
imaging agent e.g., fluorescent probes [203,206,207] or monomer
units [147] – may remain covalently attached onto the macro-
molecular structure.
Few studies on drug delivery by self-assembled polymer nanos-
tructures have accorded important to the clearance of macro-
molecules once the cargo has been released. In order to facili-
tate renal elimination, degradable polymers can be of great in-
terest (see Fig. 16B). PCL-block-[poly(5,6-benzo-2-methylene-1,3-
dioxepane)-co-poly(fructose acrylate)] was produced by a combi-
nation of ROP, RAFT and rROP. Enzymatic degradation of the mi-
celles was induced by Lipase Pseudomonas sp. with no toxicity of
the fragmentation products towards human fibroblast and breast
cancer cell lines [54].
5.4. Gene delivery
Block copolymers possessing charged segments permit the con-
jugation and stabilization of opposite-charged species and have
been largely used for the delivery of genetic material. Narain
et al. have produced a vast range of glyco-BCPs for conjugation
with plasmid DNA (pDNA) strands. The macromolecules featur-
ing a positively-charged poly(aminopropyl methacrylate) segment
were able to complex to negatively-charged pDNA, which induced
the formation of monodispersed and stable polyplex nanoparticles
with a diameter of 30–35 nm [159]. In a later study, the influence
of several parameters (e.g., molecular weight, monomer ratio and
composition, i.e. block vs. statistical copolymers) on cell toxicity,
DNA complexation and transfection were investigated. Most no-
tably, statistical glycopolymers outmatched block-type analogues in
terms of complexation with genetic material and displayed lower
cytotoxicity, but aggregated in the presence of serum proteins [71].
Tailoring the macromolecular composition with the addition of a
phosphorylcholine block, yielding so-called ‘block-statistical’ gly-
T. Pelras and K. Loos
Fig. 17. Utilization of glycopolymers for the delivery of genetic materials. (A) Complexation of pDNA strands onto gold nanoparticles functionalized with block-type glycopoly-
mers and formation of glyconanoparticles for intracellular delivery. [157], Copyright 2009. Adapted with permission from the American Chemical Society. (B) Comparative
efficiency of the cellular uptake between block-type and statistical copolymer-based glyconanoparticles. [71], Copyright 2011. Adapted with permission from Elsevier Science
Ltd.
copolymers, further enhanced the efficacy of the gene delivery vec-
tors [72].
The same authors later reported the attachment of glycopoly-
mers onto gold nanoparticles to facilitate cellular uptake. Cell toxi-
city of the bare gold-polymer hybrids was studied before transfec-
tion experiments were carried out in vitro using the nanoparticles
complexed to pDNA [156]. Further results suggested the highest
transfection efficiency for gold nanoparticles of size around 40 nm,
unfortunately accompanied by higher cytotoxicity (see Fig. 17A)
[157]. Alternatively, the glyco-BCPs were complexed to single wall
carbon nanotubes, which may possess higher cell penetration abil-
ity and hence feature more efficient transfection (see Fig. 17B)
[158].
In-lieu of linear macromolecules, Narain and coworkers have
produced a vast array of nanogels for gene complexation and de-
livery. Crucial factors such as the presence and location of charges
have to be carefully considered to maximize compatibility with
blood components and enhance the efficiency of gene delivery
[167]. While the presence of saccharide units improves cellular up-
take and gene expression, thermo-responsive units facilitate the at-
tachment of pDNA [163,164] or siRNA [165] cargo and pH-sensitive
cross-linkers permit the breakdown of the gels into their unimer
components.
5.5. Stabilization of emulsions and nanoparticles
While micellar structures based on amphiphilic glycopolymers
have been used as carriers for various therapeutics, studies have
demonstrated their potential as stabilization agents. A series of
PnBMA-block-glycopolymers have been used as surfactant in the
emulsion polymerization of nBMA without the need for further ad-
ditives. While high monomer content could not be efficiently in-
corporated, the rate of polymerization was increased compared to
surfactant-free methods [109]. The formulations were subsequently
deposited onto surfaces and incorporation of quaternized DMAEMA
into the glycopolymer segment provided anti-bacterial activity (see
Fig. 18A) [113].
Alternatively, polysaccharide-containing polymers have been
used to stabilize inorganic nanoparticles in aqueous media. For
instance, 4-arm PCL-block-glycopolymer was used to stabilize
CdTe quantum dots through absorption into their vesicular struc-
ture [172], while thiol-terminated diblocks were attached to gold
nanoparticles [123].
15
Progress in Polymer Science 117 (2021) 101393
Chen et al. have taken advantage of the electrostatic interac-
tion that exist between charged polymers to stabilize nanopar-
ticles. The authors attached a dopamine-containing polymer fea-
turing a positively-charged segment onto zinc phthalocyanine to
yield surface-charged inorganic/organic hybrid nanoparticles (see
Fig. 18B). Complexation with glyco-BCPs including a negatively-
charged PMAA segment provided a thick charge-neutral polysac-
charide shell that significantly enhanced the nanoparticles stability
in serum [56].
5.6. Nanoreactors
While most of the micelles formed from block-type glycopoly-
mers are achieved in aqueous solutions, few studies have explored
the feasibility of reverse micelles in organic media. Chen et al.
demonstrated that the high polarity change induced by the depro-
tection of a glycopolymer segment triggers assembly or even mor-
phological changes [155]. The authors have used the deacetylation
of mannose units to drive morphological changes from micelles to
“glyco-inside” vesicles. When the process was done in presence of
AuCl4 − , the shape rearrangement permitted the generation of ho-
mogeneous gold nanoparticles within the glycopolymer layer with-
out any additional reducing reagents or energy input [154].
6. Outlook
The synthetic routes for the production of glycomonomers
and their polymerization have witnessed tremendous advances, so
sequence-controlled glycopolymers have become relatively simple
to produce. The vast range of user-friendly polymerization tech-
niques has further helped the development of macromolecules
with complex chemistries and morphologies.
The recognition of glycopolymers with living organisms (e.g.,
cells, macrophages, viruses) and their low cytotoxicity make them
ideal candidates to implement into nanoparticles for targeted ther-
apeutics and gene delivery. The incorporation of other functions
such as degradable or stimuli-responsive polymer segments have
the potential to further enhance the efficiency of the delivery and
elimination of the side-products. While glyco-BCPs have mainly
found applications in nanomedicine, a handful of examples have
cleverly demonstrated their potential in other fields, including for
the stabilization of emulsions and inorganic nanoparticles.
T. Pelras and K. Loos
Fig. 18. Applications of glyco-BCPs as stabilization agents. (A) PnBMA-block-glycopolymer used for the emulsion polymerization of nBMA without further additives and
deposition onto surfaces for lectin recognition. [109], Copyright 2011. Adapted with permission from the Royal Society of Chemistry. (B) Complexation of negatively-charged
glycopolymers onto positive nanoparticles to further enhance their stability in serum. Transmission electron microscopy images of (B1) the nanoparticles and (B2) the
glycopolymer-stabilized nanoparticles and (B3) photographs of the nanoparticles in goat serum. [56], Copyright 2016. Adapted with permission from the Royal Society of
Chemistry.
Besides tree-like BCPs, there have been very few examples
of glycopolymer-based architectures featuring dense and well-
controlled segments [51,220-223]. Compartmentalized molecular
polymer brushes [224] in particular offer interesting properties
that can be taken advantage of for drug delivery [225], templat-
ing applications [226], nano-engineering [227] as well as polymer-
polymer complexation [228,229]. We anticipate the synthesis and
use of saccharide-containing macromolecules with complex de-
signs that can only be achieved through sequence-controlled poly-
merization to become more widespread in many areas of ma-
terials sciences. Additionally, we expect the synthesis of gly-
comonomers and sequence-controlled glycopolymers to go towards
more environment-friendly processes, notably through the utiliza-
tion of enzymes and water-based synthesis routes [230].
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgments
The authors wish to acknowledge financial support by a NWO-
VICI innovational research grant.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.progpolymsci.2021.
101393.
References
[1] Saxena RC, Adhikari DK, Goyal HB. Biomass-based energy fuel through bio-
chemical routes: a review. Renew Sustain Energy Rev 2009;13:167–78.
[2] Cosgrove DJ. Nanoscale structure, mechanics and growth of epidermal cell
walls. Curr Opin Plant Biol 2018;46:77–86.
[3] Domard A. A perspective on 30 years research on chitin and chitosan. Carbo-
hydr Polym 2011;84:696–703.
[4] Shoulders MD, Raines RT. Collagen Structure and Stability. Annu Rev Biochem
2009;78:929–58.
[5] Lundquist JJ, Toone EJ. The Cluster Glycoside Effect. Chem Rev
2002;102:555–78.
[6] Lutz J-F, Lehn J-M, Meijer EW, Matyjaszewski K. From precision polymers to
complex materials and systems. Nat Rev Mater 2016;1:16024.
[7] Ting SRS, Chen G, Stenzel MH. Synthesis of glycopolymers and their multiva-
lent recognitions with lectins. Polym Chem 2010;1:1392–412.
[8] Wong CK, Qiang X, Müller AHE, Gröschel AH. Self-Assembly of block copoly-
mers into internally ordered microparticles. Prog Polym Sci 2020:101211.
[9] Qiang X, Chakroun R, Janoszka N, Gröschel AH. Self-assembly of Multiblock
Copolymers. Isr J Chem 2019;59:945–58.
16
Progress in Polymer Science 117 (2021) 101393
[10] Grzelczak M, Liz-Marzán LM, Klajn R. Stimuli-responsive self-assembly of
nanoparticles. Chem Soc Rev 2019;48:1342–61.
[11] Schatz C, Lecommandoux S. Polysaccharide-containing block copolymers:
synthesis, properties and applications of an emerging family of glycoconju-
gates. Macromol Rapid Commun 2010;31:1664–84.
[12] Volokhova AS, Edgar KJ, Matson JB. Polysaccharide-containing block copoly-
mers: synthesis and applications. Mater Chem Front 2020;4:99–112.
[13] Rüde E, Westphal O, Hurwitz E, Fuchs S, Sela M. Synthesis and
antigenic properties of sugar-polypeptide conjugates. Immunochemistry
1966;3:137–51.
[14] Rüde E, Meyer-Delius M. Synthesis of the N-carboxy-α -amino acid anhydrides
of several O-acetylated serine glycosides. Carbohydr Res 1968;8:219–32.
[15] Li Z-C, Liang Y-Z, Li F-M. Multiple morphologies of aggregates from block
copolymers containing glycopolymer segments. Chem Commun 1999:1557–8.
[16] Li Z-C, Liang Y-Z, Chen G-Q, Li F-M. Synthesis of amphiphilic block copoly-
mers with well-defined glycopolymer segment by atom transfer radical poly-
merization. Macromol Rapid Commun 20 0 0;21:375–80.
[17] Gibson MI, Hunt GJ, Cameron NR. Improved synthesis of O-linked, and first
synthesis of S- linked, carbohydrate functionalised N-carboxyanhydrides (gly-
coNCAs). Org Biomol 2007;5:2756–7.
[18] Ambrosi M, Batsanov AS, Cameron NR, Davis BG, Howard JAK, Hunter R.
Influence of preparation procedure on polymer composition: synthesis
and characterisation of polymethacrylates bearing β -D-glucopyranoside and
β -D-galactopyranoside residues. J Chem Soc Perkin Trans 2002;1:45–52.
[19] Park H, Rosencrantz RR, Elling L, Böker A. glycopolymer brushes for specific
lectin binding by controlled multivalent presentation of N-Acetyllactosamine
glycan oligomers. Macromol Rapid Commun 2015;36:45–54.
[20] Labeau M-P, Cramail H, Deffieux A. Amphiphilic block copolymers of con-
trolled dimensions with hydrophilic glycosidic vinyl ether moieties. Macro-
mol Chem Phys 1998;199:335–42.
[21] Loykulnant S, Hayashi M, Hirao A. Protection and polymerization of func-
tional monomers. 28. anionic living polymerization of styrene deriva-
tives containing acetal-protected monosaccharide residues. Macromolecules
1998;31:9121–6.
[22] Loykulnant S, Hirao A. Protection and polymerization of functional
monomers. 30. Anionic living polymerization of 4-Alkylstyrenes con-
taining acetal-protected monosaccharide residues. Macromolecules
20 0 0;33:4757–64.
[23] Loykulnant S, Yamashiro M, Hirao A. Protection and polymerization of func-
tional monomers, 31. Living anionic polymerization of styrene derivatives
m,m -disubstituted with acetal-protected monosaccharide residues. Macro-
mol Chem Phys 2001;202:1791–8.
[24] Hayashi M, Loykulnant S, Hirao A, Nakahama S. Synthesis of end-function-
alized polymers by means of living anionic polymerization. 9. Synthesis
of well-defined end-functionalized polymers with one, two, three, or four
monosaccharide residues. Macromolecules 1998;31:2057–63.
[25] Hirao A, Hayashi M, Loykulnant S. Anionic living polymerization of func-
tional monomers. Precise synthesis of various functionalized polystyrenes
with monosaccharide residues by anionic living polymerization and living
functionalization reaction. Macromol Symp 20 0 0;161:45–52.
[26] Loykulnant S, Hirao A. Synthesis and characterization of well-defined
chain-end- and in-chain-functionalized polystyrenes with a definite number
of d-glucose and/or d-galactose. Macromolecules 2001;34:8434–45.
[27] Hirao A, Hayashi M, Negishi Y, Haraguchi N, Loykulnant S. Synthesis of
well-defined chain-end- and in-chain-functionalized polystyrenes with a def-
inite number of benzyl chloride moieties and D-glucose residues. Macromol
Symp 2002;181:73–94.
[28] Loykulnant S, Hirao A. New functionalized anionic initiators prepared from
substituted 1,1-Diphenylethylene derivatives with acetal-protected monosac-
T. Pelras and K. Loos
charides and their application to chain-multi-functionalized polymers with
glucose and galactose molecules. Macromol Chem Phys 2003;204:1284–96.
[29] Messina MS, Ko JH, Yang Z, Strouse MJ, Houk KN, Maynard HD. Effect
of trehalose polymer regioisomers on protein stabilization. Polym Chem
2017;8:4781–8.
[30] Lee J, Lin E-W, Lau UY, Hedrick JL, Bat E, Maynard HD. Trehalose
glycopolymers as excipients for protein stabilization. Biomacromolecules
2013;14:2561–9.
[31] Minoda M, Yamaoka K, Yamada K, Takaragi A, Miyamoto T. Synthesis of func-
tional polymers bearing pendant mono-and oligo-saccharide residues. Macro-
mol Symp 1995;99:169–77.
[32] Yamada K, Yamaoka K, Minoda M, Miyamoto T. Survey of a catalyst system
for living cationic polymerization of glucose-carrying vinyl ethers with acetyl
and isopropylidene protecting groups. Polym Int 2001;50:531–7.
[33] Yamada K, Yamaoka K, Minoda M, Miyamoto T. Controlled synthesis of am-
phiphilic block copolymers with pendant glucose residues by living cationic
polymerization. J Polym Sci Part A Polym Chem 1997;35:255–61.
[34] Yamada K, Minoda M, Fukuda T, Miyamoto T. Amphiphilic block and statis-
tical copolymers with pendant glucose residues: Controlled synthesis by liv-
ing cationic polymerization and the effect of copolymer architecture on their
properties. J Polym Sci Part A Polym Chem 2001;39:459–67.
[35] Yamada K, Minoda M, Miyamoto T. Controlled synthesis of amphiphilic
block copolymers with pendant N-Acetyl-d-glucosamine residues by liv-
ing cationic polymerization and their interaction with WGA lectin. Macro-
molecules 1999;32:3553–8.
[36] Pearson S, Vitucci D, Khine YY, Dag A, Lu H, Save M, Billon L, Stenzel MH.
Light-responsive azobenzene-based glycopolymer micelles for targeted drug
delivery to melanoma cells. Eur Polym J 2015;69:616–27.
[37] Ye W, Wells S, DeSimone JM. Well-defined glycopolymer amphiphiles for liq-
uid and supercritical carbon dioxide applications. J Polym Sci Part A Polym
Chem 2001;39:3841–9.
[38] Xiao N-Y, Li A-L, Liang H, Lu J. A well-defined novel aldehyde-functionalized
glycopolymer: synthesis, micelle formation, and its protein immobilization.
Macromolecules 2008;41:2374–80.
[39] Xiao N, Liang H, Lu J. Degradable and biocompatible aldehyde-functionalized
glycopolymer conjugated with doxorubicinvia acid-labile Schiff base linkage
for pH-triggered drug release. Soft Matter 2011;7:10834–40.
[40] Narumi A, Kaga H, Kawasaki K, Taniguchi Y, Satoh T, Kakuchi T. Glycoconju-
gated polymer. I. Synthesis and characterization of amphiphilic polystyrenes
with glucose, maltose, and maltohexaose as hydrophilic segments. J Polym
Sci Part A Polym Chem 2001;39:4061–7.
[41] León O, Bordegé V, Muñoz-Bonilla A, Sánchez-Chaves M, Fernández-Gar-
cía M. Well-controlled amphiphilic block glycopolymers and their molec-
ular recognition with lectins. J Polym Sci Part A Polym Chem 2010;48:
3623–3631.
[42] Kloosterman WMJ, Roest S, Priatna SR, Stavila E, Loos K. Chemo-enzymatic
synthesis route to poly(glucosyl-acrylates) using glucosidase from almonds.
Green Chem 2014;16:1837–46.
[43] Adharis A, Loos K. Green synthesis of glycopolymers using an enzymatic ap-
proach. Macromol Chem Phys 2019;220:1900219.
[44] Adharis A, Vesper D, Koning N, Loos K. Synthesis of (meth)acrylamide-based
glycomonomers using renewable resources and their polymerization in aque-
ous systems. Green Chem 2018;20:476–84.
[45] López Donaire ML, Parra-Cáceres J, Vázquez-Lasa B, García-Álvarez I, Fer-
nández-Mayoralas A, López-Bravo A, San Román J. Polymeric drugs based
on bioactive glycosides for the treatment of brain tumours. Biomaterials
2009;30:1613–26.
[46] López-Donaire ML, Sussman EM, Fernández-Gutiérrez M, Méndez-Vilas A,
Ratner BD, Vázquez-Lasa B, San Román J. Amphiphilic self-assembled “Poly-
meric Drugs”: morphology, properties, and biological behavior of nanoparti-
cles. Biomacromolecules 2012;13:624–35.
[47] Kloosterman WMJ, Jovanovic D, Brouwer SGM, Loos K. Amylase catalyzed
synthesis of glycosyl acrylates and their polymerization. Green Chem
2014;16:203–10.
[48] Kloosterman WMJ, Brouwer SGM, Loos K. Enzyme-catalyzed synthesis of
saccharide acrylate monomers from nonedible biomass. Chem Asian J
2014;9:2156–61.
[49] Adharis A, Petrović DM, Özdamar I, Woortman AJJ, Loos K. Environmentally
friendly pathways towards the synthesis of vinyl-based oligocelluloses. Car-
bohydr Polym 2018;193:196–204.
[50] Kloosterman WMJ, Spoelstra-van Dijk G, Loos K. Biocatalytic synthesis of mal-
todextrin-based acrylates from starch and α -Cyclodextrin. Macromol Biosci
2014;14:1268–79.
[51] Fleet R, van den Dungen E, Klumperman B. Synthesis of novel glycopolymer
brushes via a combination of RAFT-mediated polymerisation and ATRP. S Afr
J Sci 2011;107:424.
[52] Fraser C, Grubbs RH. Synthesis of glycopolymers of controlled molecu-
lar weight by ring-opening metathesis polymerization using well-defined
functional group tolerant ruthenium carbene catalysts. Macromolecules
1995;28:7248–55.
[53] Nomura K, Schrock RR. Preparation of “Sugar-Coated” homopolymers and
multiblock ROMP copolymers. Macromolecules 1996;29:540–5.
[54] Ganda S, Jiang Y, Thomas DS, Eliezar J, Stenzel MH. Biodegradable glycopoly-
meric micelles obtained by RAFT-controlled radical ring-opening polymeriza-
tion. Macromolecules 2016;49:4136–46.
17
Progress in Polymer Science 117 (2021) 101393
[55] Zhao J, Babiuch K, Lu H, Dag A, Gottschaldt M, Stenzel MH. Fructose-coated
nanoparticles: a promising drug nanocarrier for triple-negative breast cancer
therapy. Chem Commun 2014;50:15928–31.
[56] Chen K, Bao M, Muñoz Bonilla A, Zhang W, Chen G. A biomimicking and elec-
trostatic self-assembly strategy for the preparation of glycopolymer decorated
photoactive nanoparticles. Polym Chem 2016;7:2565–72.
[57] Ting SRS, Min EH, Zetterlund PB, Stenzel MH. Controlled/living ab initio emul-
sion polymerization via a glucose RAFTstab: Degradable cross-linked glyco–
particles for concanavalin A/FimH conjugations to cluster E. coli bacteria.
Macromolecules 2010;43:5211–21.
[58] Menon S, Das S. A photoresponsive fluorescent glycopolymer. Polym Chem
2012;3:2619–24.
[59] Kramer JR, Deming TJ. Glycopolypeptides via living polymerization of Glyco-
sylated-l-lysine N-Carboxyanhydrides. J Am Chem Soc 2010;132:15068–71.
[60] Akai S, Kajihara Y, Nagashima Y, Kamei M, Arai J, Bito M, Sato K-i. Synthesis
of nez glycopolymers containing β -D-Mannopyranose, and C-2-Substituted
β -D-Mannopyrannose residues as a new class of inhibitor. J Carbohydr Chem
2001;20:121–43.
[61] Manning DD, Strong LE, Hu X, Beck PJ, Kiessling LL. Neoglycopolymer in-
hibitors of the selectins. Tetrahedron 1997;53:11937–52.
[62] Chen Y, Wulff G. Amphiphilic block copolymers with pendent sugar as
hydrophilic segments and their surface properties. Macromol Chem Phys
2001;202:3273–8.
[63] Chen Y, Wulff G. Synthesis of poly(styryl sugar)s by TEMPO mediated free
radical polymerization. Macromol Chem Phys 2001;202:3426–31.
[64] Wulff G, Clarkson G. New type of polyvinylsaccharides with
N,N-dimethylbarbituric acid as a linker between sugar and styrene residue.
Macromol Chem Phys 1994;195:2603–10.
[65] Saha S, Klein-Hitpaß M, Vallet C, Knauer SK, Schmuck C, Voskuhl J, Giese M.
Smart glycopolymeric nanoparticles for multivalent lectin binding and stim-
uli-controlled guest release. Biomacromolecules 2020;21:2356–64.
[66] Yilmaz G, Guler E, Geyik C, Demir B, Ozkan M, Odaci Demirkol D, Ozcelik S,
Timur S, Becer CR. pH responsive glycopolymer nanoparticles for targeted de-
livery of anti-cancer drugs. Mol Syst Des Eng 2018;3:150–8.
[67] Krannig K-S, Doriti A, Schlaad H. Facilitated synthesis of heterofunctional gly-
copolypeptides. Macromolecules 2014;47:2536–9.
[68] Kramer JR, Deming TJ. Glycopolypeptides with a redox-triggered helix-to-coil
transition. J Am Chem Soc 2012;134:4112–15.
[69] Ladmiral V, Semsarilar M, Canton I, Armes SP. Polymerization-induced self-
-assembly of galactose-functionalized biocompatible diblock copolymers for
intracellular delivery. J Am Chem Soc 2013;135:13574–81.
[70] Kobayashi K, Sumitomo H, Ina Y. Synthesis and functions of polystyrene
derivatives having pendant oligosaccharides. Polym J 1985;17:567–75.
[71] Ahmed M, Narain R. The effect of polymer architecture, composition, and
molecular weight on the properties of glycopolymer-based non-viral gene de-
livery systems. Biomaterials 2011;32:5279–90.
[72] Ahmed M, Jawanda M, Ishihara K, Narain R. Impact of the nature, size and
chain topologies of carbohydrate–phosphorylcholine polymeric gene delivery
systems. Biomaterials 2012;33:7858–70.
[73] Stöhr T, Blaudszun A-R, Steinfeld U, Wenz G. Synthesis of glycosylated pep-
tides by NCA polymerization for recognition of human T-cells. Polym Chem
2011;2:2239–48.
[74] Zhou W-J, Wilson ME, Kurth MJ, Hsieh Y-L, Krochta JM, Shoemaker CF. Syn-
thesis and properties of a novel water-soluble lactose-containing polymer and
its cross-linked hydrogel. Macromolecules 1997;30:7063–8.
[75] Pati D, Shaikh AY, Hotha S, Gupta SS. Synthesis of glycopolypeptides by the
ring opening polymerization of O-glycosylated-α -amino acid N-carboxyanhy-
dride (NCA). Polym Chem 2011;2:805–11.
[76] Muñoz-Bonilla A, León O, Cerrada ML, Rodríguez-Hernández J,
Sánchez-Chaves M, Fernández-García M. Chemical modification of block
copolymers based on 2-hydroxyethyl acrylate to obtain amphiphilic gly-
copolymers. Eur Polym J 2015;62:167–78.
[77] Alvárez-Paino M, Juan-Rodríguez R, Cuervo-Rodríguez R, Muñoz-Bonilla A,
Fernández-García M. Preparation of amphiphilic glycopolymers with flexible
long side chain and their use as stabilizer for emulsion polymerization. J Col-
loid Interface Sci 2014;417:336–45.
[78] Muñoz-Bonilla A, Bordegé V, León O, Cuervo-Rodríguez R, Sánchez-Chaves M,
Fernández-García M. Influence of glycopolymers structure on the copolymer-
ization reaction and on their binding behavior with lectins. Eur Polym J
2012;48:963–73.
[79] Kanai M, Mortell KH, Kiessling LL. Varying the size of multivalent ligands:
the dependence of concanavalin A binding on neoglycopolymer length. J Am
Chem Soc 1997;119:9931–2.
[80] Schuster MC, Mortell KH, Hegeman AD, Kiessling LL. Neoglycopolymers
produced by aqueous ring-opening metathesis polymerization: decreas-
ing saccharide density increases activity. J Mol Catal A Chem 1997;116:
209–216.
[81] Hirao A, Goseki R, Ishizone T. Advances in living anionic polymerization: from
functional monomers, polymerization systems, to macromolecular architec-
tures. Macromolecules 2014;47:1883–905.
[82] Aoshima S, Kanaoka S. A renaissance in living cationic polymerization. Chem
Rev 2009;109:5245–87.
[83] Sutthasupa S, Shiotsuki M, Sanda F. Recent advances in ring-opening
metathesis polymerization, and application to synthesis of functional mate-
rials. Polym J 2010;42:905–15.
T. Pelras and K. Loos
[84] Hu M, Najdi SD, Wu KJ, Kurth MJ. Aqueous vinyl-insertion polymerization of
lactamine-functionalized norbornene by palladium(II) chloride. Tetrahedron
Lett 2002;43:1775–8.
[85] Ogawa KA, Goetz AE, Boydston AJ. Metal-free ring-opening metathesis poly-
merization. J Am Chem Soc 2015;137:1400–3.
[86] Lu H, Wang J, Song Z, Yin L, Zhang Y, Tang H, Tu C, Lin Y, Cheng J. Re-
cent advances in amino acid N-carboxyanhydrides and synthetic polypep-
tides: chemistry, self-assembly and biological applications. Chem Commun
2014;50:139–55.
[87] Kramer JR, Deming TJ. Recent advances in glycopolypeptide synthesis. Polym
Chem 2014;5:671–82.
[88] Deming TJ. Synthesis of Side-Chain Modified Polypeptides. Chem Rev
2016;116:786–808.
[89] Aoi K, Tsutsumiuchi K, Okada M. Glycopeptide synthesis by an .alpha.-Amino
Acid N-Carboxyanhydride (NCA) method: ring-opening polymerization of a
sugar-substituted NCA. Macromolecules 1994;27:875–7.
[90] Tsutsumiuchi K, Aoi K, Okada M. Synthesis of Polyoxazoline−(Glyco)peptide
block copolymers by ring-opening polymerization of (sugar-substituted)
α -Amino Acid N-Carboxyanhydrides with polyoxazoline macroinitiators.
Macromolecules 1997;30:4013–17.
[91] Aoi K, Itoh K, Okada M. Globular carbohydrate macromolecules "Sugar Balls".
1. Synthesis of novel sugar-persubstituted poly(amido amine) dendrimers.
Macromolecules 1995;28:5391–3.
[92] Aoi K, Tsutsumiuchi K, Yamamoto A, Okada M. Globular carbohydrate macro-
molecule “sugar balls” 3. “Radial-growth polymerization” of sugar-substituted
α -amino acid N-carboxyanhydrides (glycoNCAs) with a dendritic initiator.
Tetrahedron 1997;53:15415–27.
[93] Tsutsumiuchi K, Aoi K, Okada M. Synthesis of novel glycopeptide-polyoxazo-
line block copolymers by direct coupling between living anionic and cationic
polymerization systems. Macromol Rapid Commun 1995;16:749–55.
[94] Pati D, Kalva N, Das S, Kumaraswamy G, Sen Gupta S, Ambade AV. Mul-
tiple topologies from glycopolypeptide–dendron conjugate self-assembly:
nanorods, micelles, and organogels. J Am Chem Soc 2012;134:7796–802.
[95] Deming TJ. Cobalt and iron initiators for the controlled polymerization of
α -Amino Acid-N-Carboxyanhydrides. Macromolecules 1999;32:4500–2.
[96] Cha JN, Stucky GD, Morse DE, Deming TJ. Biomimetic synthesis of ordered
silica structures mediated by block copolypeptides. Nature 20 0 0;403:289–92.
[97] Kramer JR, Rodriguez AR, Choe U-J, Kamei DT, Deming TJ. Glycopolypep-
tide conformations in bioactive block copolymer assemblies influence their
nanoscale morphology. Soft Matter 2013;9:3389–95.
[98] Hořejší V, Kocourek J. In: Kaplan NP, Colowick NP, Jakoby WB, Wilchek M,
editors. [36]O-Glycosyl polyacrylamide gels: Application to phytohemagglu-
tinins. Cambridge: Academic Press; 1974. p. 361–7.
[99] Hořejší V, Smolek P, Kocourek J. Studies on lectins XXXV. Water-soluble
O-glycosyl polyacrylamide derivatives for specific precipitation of lectins.
Biochim Biophys Acta 1978;538:293–8.
[100] Hořejší V, Kocourek J. Studies on phytohemagglutinins XII. O-glycosyl poly-
acrylamide gels for affinity chromatography of phytohemagglutinins. Biochim
Biophys Acta 1973;297:346–51.
[101] Tagawa K, Sendai N, Ohno K, Kawaguchi T, Kitano H, Matsunaga T. Recogni-
tion of novel amphiphiles with many pendent mannose residues by Con A.
Bioconjug Chem 1999;10:354–60.
[102] Matyjaszewski K. Atom Transfer Radical Polymerization (ATRP): current sta-
tus and future perspectives. Macromolecules 2012;45:4015–39.
[103] Discekici EH, Anastasaki A, Read de Alaniz J, Hawker CJ. Evolution and fu-
ture directions of metal-free atom transfer radical polymerization. Macro-
molecules 2018;51:7421–34.
[104] Liang Y-Z, Li Z-C, Li F-M. Multiple morphologies of molecular assemblies
formed by polystyrene-block-poly[2-(β -D-glucopyranosyloxy)ethyl acrylate]
in water. New J Chem 20 0 0;24:323–8.
[105] Liang Y-Z, Li Z-C, Li F-M. Morphological behavior for micelle from
Polystyrene-b-poly[2-(β -D-glucopyranosyloxy)ethyl acrylate] upon changing
the copolymer concentration. Chem Lett 20 0 0;29:320–1.
[106] Li Z-C, Shen Y, Liang Y-Z, Li F-M. Morphological transition between vesicles
and tubules for a glycopolymer-containing amphiphilic diblock copolymer in
aqueous solutions. Chin J Polym Sci 2001;19:297–301.
[107] Li Z-C, Liang Y-Z, Li F-M. Additives induced morphological transition of
molecular assemblies from PS-b-PGEA in aqueous solutions. New J Chem
2002;26:1805–10.
[108] Ohno K, Tsujii Y, Fukuda T. Synthesis of a well-defined glycopolymer by
atom transfer radical polymerization. J Polym Sci Part A Polym Chem
1998;36:2473–81.
[109] Muñoz-Bonilla A, Heuts JPA, Fernández-García M. Glycoparticles and bioac-
tive films prepared by emulsion polymerization using a well-defined block
glycopolymer stabilizer. Soft Matter 2011;7:2493–9.
[110] León O, Muñoz-Bonilla A, Bordegé V, Sánchez-Chaves M, Fernández-García M.
Amphiphilic block glycopolymers via atom transfer radical polymerization:
Synthesis, self-assembly and biomolecular recognition. J Polym Sci Part A
Polym Chem 2011;49:2627–35.
[111] Muñoz-Bonilla A, León O, Bordegé V, Sánchez-Chaves M, Fernández-García M.
Controlled block glycopolymers able to bind specific proteins. J Polym Sci Part
A Polym Chem 2013;51:1337–47.
[112] Álvarez-Paino M, Muñoz-Bonilla A, López-Fabal F, Gómez-Garcés JL,
Heuts JPA, Fernández-García M. Effect of glycounits on the antimicrobial
properties and toxicity behavior of polymers based on quaternized DMAEMA.
Biomacromolecules 2015;16:295–303.
18
Progress in Polymer Science 117 (2021) 101393
[113] Álvarez-Paino M, Muñoz-Bonilla A, López-Fabal F, Gómez-Garcés JL,
Heuts JPA, Fernández-García M. Functional surfaces obtained from emulsion
polymerization using antimicrobial glycosylated block copolymers as surfac-
tants. Polym Chem 2015;6:6171–81.
[114] Park H, Walta S, Rosencrantz RR, Körner A, Schulte C, Elling L, Richtering W,
Böker A. Micelles from self-assembled double-hydrophilic PHEMA-glycopoly-
mer-diblock copolymers as multivalent scaffolds for lectin binding. Polym
Chem 2016;7:878–86.
[115] Pasparakis G, Alexander C. Sweet talking double hydrophilic block copolymer
vesicles. Angew Chem Int Ed 2008;47:4847–50.
[116] Menon S, Ongungal RM, Das S. Photocleavable glycopolymer aggregates.
Polym Chem 2013;4:623–8.
[117] Narain R, Armes SP. Synthesis of low polydispersity, controlled-structure
sugar methacrylate polymers under mild conditions without protecting group
chemistry. Chem Commun 2002:2776–7.
[118] Narain R, Armes SP. Synthesis and aqueous solution properties of novel
sugar methacrylate-based homopolymers and block copolymers. Biomacro-
molecules 2003;4:1746–58.
[119] Narain R, Armes SP. Direct synthesis and aqueous solution proper-
ties of well-defined cyclic sugar methacrylate polymers. Macromolecules
2003;36:4675–8.
[120] You L-C, Lu F-Z, Li Z-C, Zhang W, Li F-M. Glucose-sensitive aggregates formed
by poly(ethylene oxide)-block-poly(2-glucosyl- oxyethyl acrylate) with Con-
canavalin A in dilute aqueous medium. Macromolecules 2003;36:1–4.
[121] Xiao Y, Sun H, Du J. Sugar-breathing glycopolymersomes for regulating glu-
cose level. J Am Chem Soc 2017;139:7640–7.
[122] Dai X-H, Dong C-M, Yan D. Supramolecular and biomimetic polypseudorotax-
ane/glycopolymer biohybrids: synthesis, glucose-surfaced nanoparticles, and
recognition with lectin. J Phys Chem B 2008;112:3644–52.
[123] Pei D, Li Y, Huang Q, Ren Q, Li F, Shi T. Biomimetic glycopolymers tethered
gold nanoparticles: preparation, self-assembly and lectin recognition proper-
ties. Colloids Surf B 2015;126:367–73.
[124] Lu F-Z, Meng J-Q, Du F-S, Li Z-C, Zhang B-Y. Pyrene end-labeled di-
block glycopolymers: synthesis and aggregation. Macromol Chem Phys
2005;206:513–20.
[125] Dai X-H, Dong C-M. Synthesis, self-assembly and recognition properties of
biomimetic star-shaped poly(ε -caprolactone)-b-glycopolymer block copoly-
mers. J Polym Sci Part A Polym Chem 2008;46:817–29.
[126] Dai X-H, Zhang H-D, Dong C-M. Fabrication, biomolecular binding, in
vitro drug release behavior of sugar-installed nanoparticles from star
poly(ɛ-caprolactone)/glycopolymer biohybrid with a dendrimer core. Polymer
2009;50:4626–34.
[127] Zhou W, Dai X-H, Dong C-M. Biodegradable and biomimetic
poly(ε -caprolactone)/poly(lactobionamidoethyl methacrylate) biohybrids:
synthesis, lactose-installed nanoparticles and recognition properties. Macro-
mol Biosci 2008;8:268–78.
[128] Qiu S, Huang H, Dai X-H, Zhou W, Dong C-M. Star-shaped polypep-
tide/glycopolymer biohybrids: synthesis, self-assembly, biomolecular recogni-
tion, and controlled drug release behavior. J Polym Sci Part A Polym Chem
20 09;47:20 09–23.
[129] Mansfield KM, Maynard HD. Site-specific insulin-trehalose glycopolymer
conjugate by grafting from strategy improves bioactivity. ACS Macro Lett
2018;7:324–9.
[130] Hardy JG, Pfaff A, Leal-Egaña A, Müller AHE, Scheibel TR. Glycopolymer func-
tionalization of engineered spider silk protein-based materials for improved
cell adhesion. Macromol Biosci 2014;14:936–42.
[131] Gupta SS, Raja KS, Kaltgrad E, Strable E, Finn MG. Virus–glycopolymer con-
jugates by copper(i) catalysis of atom transfer radical polymerization and
azide–alkyne cycloaddition. Chem Commun 2005:4315–17.
[132] Dong C-M, Sun X-L, Faucher KM, Apkarian RP, Chaikof EL. Synthesis and
characterization of glycopolymer-polypeptide triblock copolymers. Biomacro-
molecules 2004;5:224–31.
[133] Dong C-M, Chaikof EL. Self-assembled nanostructures of a biomimetic
glycopolymer–polypeptide triblock copolymer. Colloid Polym Sci
2005;283:1366–70.
[134] Dong C-M, Faucher KM, Chaikof EL. Synthesis and properties of biomimetic
poly(L-glutamate)-b-poly(2-acryloyloxyethyllactoside)-b-poly(L-glutamate)
triblock copolymers. J Polym Sci Part A Polym Chem 2004;42:5754–65.
[135] Percec V, Popov AV, Ramirez-Castillo E, Monteiro M, Barboiu B, Weichold O,
Asandei AD, Mitchell CM. Aqueous room temperature metal-catalyzed living
radical polymerization of vinyl chloride. J Am Chem Soc 2002;124:4940–1.
[136] Percec V, Guliashvili T, Ladislaw JS, Wistrand A, Stjerndahl A, Sienkowska MJ,
et al. Ultrafast synthesis of ultrahigh molar mass polymers by metal-cat-
alyzed living radical polymerization of acrylates, methacrylates, and vinyl
chloride mediated by SET at 25 °C. J Am Chem Soc 2006;128:14156–65.
[137] Anastasaki A, Nikolaou V, Haddleton DM. Cu(0)-mediated living radical poly-
merization: recent highlights and applications; a perspective. Polym Chem
2016;7:1002–26.
[138] Zhang Q, Wilson P, Anastasaki A, McHale R, Haddleton DM. Synthesis and ag-
gregation of double hydrophilic diblock glycopolymers via aqueous SET-LRP.
ACS Macro Lett 2014;3:491–5.
[139] Zhang Q, Collins J, Anastasaki A, Wallis R, Mitchell DA, Becer CR,
Haddleton DM. Sequence-controlled multi-block glycopolymers to inhibit
DC-SIGN-gp120 binding. Angew Chem Int Ed 2013;52:4435–9.
[140] Perrier S. 50th anniversary perspective: RAFT polymerization—a user guide.
Macromolecules 2017;50:7433–47.
T. Pelras and K. Loos
[141] Moad G, Rizzardo E, Thang SH. Living radical polymerization by the RAFT pro-
cess – a third update. Aust J Chem 2012;65:985–1076.
[142] Nasiri M, Reineke TM. Sustainable glucose-based block copolymers exhibit
elastomeric and adhesive behavior. Polym Chem 2016;7:5233–40.
[143] Piloni A, Walther A, Stenzel MH. Compartmentalized nanoparticles in aque-
ous solution through hierarchical self-assembly of triblock glycopolymers.
Polym Chem 2018;9:4132–42.
[144] Hetzer M, Chen G, Barner-Kowollik C, Stenzel MH. Neoglycopolymers based
on 4-Vinyl-1,2,3-Triazole Monomers prepared by click chemistry. Macromol
Biosci 2010;10:119–26.
[145] Wang Y, Kotsuchibashi Y, Liu Y, Narain R. Study of bacterial adhesion on
biomimetic temperature responsive glycopolymer surfaces. ACS Appl Mater
Interfaces 2015;7:1652–61.
[146] Pearson S, Allen N, Stenzel MH. Core-shell particles with glycopolymer shell
and polynucleoside core via RAFT: from micelles to rods. J Polym Sci Part A
Polym Chem 2009;47:1706–23.
[147] Pfaff A, Schallon A, Ruhland TM, Majewski AP, Schmalz H, Freitag R,
Müller AHE. Magnetic and fluorescent glycopolymer hybrid nanoparticles for
intranuclear optical imaging. Biomacromolecules 2011;12:3805–11.
[148] Cao C, Zhao J, Lu M, Garvey CJ, Stenzel MH. Correlation between drug load-
ing content and biological activity: the complexity demonstrated in paclitax-
el-loaded glycopolymer micelle system. Biomacromolecules 2019;20:1545–54.
[149] Procházková E, Cao C, Rawal A, Dračínský M, Bhattacharyya S, Císařová I,
Hook JM, Stenzel MH. Polymorphic transformation of drugs induced by gly-
copolymeric vesicles designed for anticancer therapy probed by solid-state
NMR spectroscopy. ACS Appl Mater Interfaces 2019;11:28278–88.
[150] Cao C, Zhao J, Chen F, Lu M, Khine YY, Macmillan A, Garvey CJ, Stenzel MH.
Drug-induced morphology transition of self-assembled glycopolymers: in-
sight into the drug–polymer interaction. Chem Mater 2018;30:5227–36.
[151] Wong CK, Chen F, Walther A, Stenzel MH. Bioactive patchy nanoparticles with
compartmentalized cargoes for simultaneous and trackable delivery. Angew
Chem Int Ed 2019;58:7335–40.
[152] Wong CK, Heidelmann M, Dulle M, Qiang X, Förster S, Stenzel MH,
Gröschel AH. Vesicular polymer hexosomes exhibit topological defects. J Am
Chem Soc 2020;142:10989–95.
[153] Yan X, La Padula V, Favre-Bonte S, Bernard J. Heptyl mannose decorated gly-
conanoparticles with tunable morphologies through polymerization induced
self-assembly. Synthesis, functionalization and interactions with type 1 pili-
ated E. coli. Eur Polym J 2019;112:170–5.
[154] Su L, Wang C, Polzer F, Lu Y, Chen G, Jiang M. Glyco-inside micelles and
vesicles directed by protection–deprotection chemistry. ACS Macro Letters
2014;3:534–9.
[155] Wu X, Su L, Chen G, Jiang M. Deprotection-induced micellization of
glycopolymers: control of kinetics and morphologies. Macromolecules
2015;48:3705–12.
[156] Ahmed M, Deng Z, Liu S, Lafrenie R, Kumar A, Narain R. Cationic glyco-
nanoparticles: their complexation with DNA, cellular uptake, and transfection
efficiencies. Bioconjug Chem 2009;20:2169–76.
[157] Ahmed M, Deng Z, Narain R. Study of transfection efficiencies of cationic gly-
conanoparticles of different sizes in human cell line. ACS Appl Mater Inter-
faces 2009;1:1980–7.
[158] Ahmed M, Jiang X, Deng Z, Narain R. Cationic glyco-functionalized sin-
gle-walled carbon nanotubes as efficient gene delivery vehicles. Bioconjug
Chem 2009;20:2017–22.
[159] Deng Z, Ahmed M, Narain R. Novel well-defined glycopolymers synthesized
via the reversible addition fragmentation chain transfer process in aqueous
media. J Polym Sci Part A Polym Chem 2009;47:614–27.
[160] Deng Z, Li S, Jiang X, Narain R. Well-defined galactose-containing multi-func-
tional copolymers and glyconanoparticles for biomolecular recognition pro-
cesses. Macromolecules 2009;42:6393–405.
[161] Adharis A, Ketelaar T, Komarudin AG, Loos K. Synthesis and self-assembly of
double-hydrophilic and amphiphilic block glycopolymers. Biomacromolecules
2019;20:1325–33.
[162] Albertin L, Wolnik A, Ghadban A, Dubreuil F. Aqueous RAFT polymeriza-
tion of N-Acryloylmorpholine, synthesis of an ABA triblock glycopolymer
and study of its self-association behavior. Macromol Chem Phys 2012;213:
1768–1782.
[163] Ahmed M, Narain R. Intracellular delivery of DNA and enzyme in active form
using degradable carbohydrate-based nanogels. Mol Pharma 2012;9:3160–70.
[164] Sunasee R, Wattanaarsakit P, Ahmed M, Lollmahomed FB, Narain R.
Biodegradable and nontoxic nanogels as nonviral gene delivery systems. Bio-
conjug Chem 2012;23:1925–33.
[165] Ahmed M, Wattanaarsakit P, Narain R. Cationic glyco-nanogels for epidermal
growth factor receptor (EGFR) specific siRNA delivery in ovarian cancer cells.
Polym Chem 2013;4:3829–36.
[166] Quan S, Wang Y, Zhou A, Kumar P, Narain R. Galactose-based thermosensi-
tive nanogels for targeted drug delivery of Iodoazomycin Arabinofuranoside
(IAZA) for theranostic management of hypoxic hepatocellular carcinoma.
Biomacromolecules 2015;16:1978–86.
[167] Narain R, Wang Y, Ahmed M, Lai BFL, Kizhakkedathu JN. Blood compo-
nents interactions to ionic and nonionic glyconanogels. Biomacromolecules
2015;16:2990–7.
[168] Lu M, Khine YY, Chen F, Cao C, Garvey CJ, Lu H, Stenzel MH. Sugar concen-
tration and arrangement on the surface of glycopolymer micelles affect the
interaction with cancer cells. Biomacromolecules 2019;20:273–84.
19
Progress in Polymer Science 117 (2021) 101393
[169] Lu M, Chen F, Noy J-M, Lu H, Stenzel MH. Enhanced antimetastatic activity
of the ruthenium anticancer drug RAPTA-C delivered in fructose-coated mi-
celles. Macromol Biosci 2017;17:1600513.
[170] Ting SRS, Gregory AM, Stenzel MH. Polygalactose containing nanocages: The
RAFT process for the synthesis of hollow sugar balls. Biomacromolecules
2009;10:342–52.
[171] Xing T, Yang X, Fu L, Yan L. Near infrared fluorescence probe and galactose
conjugated amphiphilic copolymer for bioimaging of HepG2 cells and endo-
cytosis. Polym Chem 2013;4:4442–9.
[172] Pei D, Li Y, Huang Q, Ren Q, Li F, Shi T. Quantum dots encapsulated glycopoly-
mer vesicles: synthesis, lectin recognition and photoluminescent properties.
Colloids Surf B 2015;127:130–6.
[173] Wang X, Liu L, Luo Y, Shi H, Li J, Zhao H. Comb-shaped glycopolymer/peptide
bioconjugates by combination of RAFT polymerization and thiol-ene “Click”
chemistry. Macromol Biosci 2012;12:1575–82.
[174] Luo Y, Liu L, Wang X, Shi H, Lv W, Li J. Sugar-installed thermorespon-
sive micellar aggregates self-assembled from “coil-comb-coil” triblock gly-
copolymers: preparation and recognition with Concanavalin A. Soft Matter
2012;8:1634–42.
[175] Liau WT, Bonduelle C, Brochet M, Lecommandoux S, Kasko AM. Synthesis,
characterization, and biological interaction of glyconanoparticles with con-
trolled branching. Biomacromolecules 2015;16:284–94.
[176] Idota N, Ebara M, Kotsuchibashi Y, Narain R, Aoyagi T. Novel temperature-re-
sponsive polymer brushes with carbohydrate residues facilitate selective ad-
hesion and collection of hepatocytes. Sci Technol Adv Mater 2012;13:064206.
[177] Stenzel MH, Zhang L, Huck WTS. Temperature-responsive glycopolymer
brushes synthesized via RAFT polymerization using the Z-group approach.
Macromol Rapid Commun 2006;27:1121–6.
[178] Grubbs RB. Nitroxide-mediated radical polymerization: limitations and versa-
tility. Polym Rev 2011;51:104–37.
[179] Narumi A, Satoh T, Kaga H, Kakuchi T. Glycoconjugated polymer. 3. Synthesis
and amphiphilic property of core-glycoconjugated star-shaped polystyrene.
Macromolecules 2002;35:699–705.
[180] Ohno K, Fukuda T, Kitano H. Free radical polymerization of a sugar residue–
carrying styryl monomer with a lipophilic alkoxyamine initiator: synthesis of
a well-defined novel glycolipid. Macromol Chem Phys 1998;199:2193–7.
[181] Götz H, Harth E, Schiller SM, Frank CW, Knoll W, Hawker CJ. Synthesis
of lipo-glycopolymer amphiphiles by nitroxide-mediated living free-radical
polymerization. J Polym Sci Part A Polym Chem 2002;40:3379–91.
[182] Ohno K, Izu Y, Yamamoto S, Miyamoto T, Fukuda T. Nitroxide-controlled
free radical polymerization of a sugar-carrying acryloyl monomer. Macromol
Chem Phys 1999;200:1619–25.
[183] Ting SRS, Min EH, Escalé P, Save M, Billon L, Stenzel MH. Lectin recog-
nizable biomaterials synthesized via nitroxide-mediated polymerization of a
methacryloyl galactose monomer. Macromolecules 2009;42:9422–34.
[184] Gauthier MA, Gibson MI, Klok H-A. Synthesis of functional polymers by
post-polymerization modification. Angew Chem Int Ed 2009;48:48–58.
[185] Huang J, Bonduelle C, Thévenot J, Lecommandoux S, Heise A. Biologi-
cally active polymersomes from amphiphilic glycopeptides. J Am Chem Soc
2012;134:119–22.
[186] Bonduelle C, Huang J, Mena-Barragán T, Ortiz Mellet C, Decroocq C, Etamé E,
Heise A, Compain P, Lecommandoux S. Iminosugar-based glycopolypeptides:
glycosidase inhibition with bioinspired glycoprotein analogue micellar self-
-assemblies. Chem Commun 2014;50:3350–2.
[187] Bonduelle C, Oliveira H, Gauche C, Huang J, Heise A, Lecommandoux S. Mul-
tivalent effect of glycopolypeptide based nanoparticles for galectin binding.
Chem Commun 2016;52:11251–4.
[188] Bonduelle C, Huang J, Ibarboure E, Heise A, Lecommandoux S. Synthesis and
self-assembly of “tree-like” amphiphilic glycopolypeptides. Chem Commun
2012;48:8353–5.
[189] Bonduelle C, Mazzaferro S, Huang J, Lambert O, Heise A, Lecommandoux S.
Synthesis and self-assembly of branched glycopolypeptides: effect of topology
and conformation. Faraday Discussions 2013;166:137–50.
[190] Peyret A, Trant JF, Bonduelle CV, Ferji K, Jain N, Lecommandoux S,
Gillies ER. Synthetic glycopolypeptides: synthesis and self-assembly of
poly(γ -benzyl-l-glutamate)-glycosylated dendron hybrids. Polym Chem
2015;6:7902–12.
[191] Gauche C, Lecommandoux S. Versatile design of amphiphilic glycopolypep-
tides nanoparticles for lectin recognition. Polymer 2016;107:474–84.
[192] Li Z, Zhang Y, Wu L, Yu W, Wilks TR, Dove AP, H-m Ding, O’Reilly RK, Chen G,
Jiang M. Glyco-platelets with controlled morphologies via crystallization–
driven self-assembly and their shape-dependent interplay with macrophages.
ACS Macro Lett 2019;8:596–602.
[193] Su L, Zhang W, Wu X, Zhang Y, Chen X, Liu G, Chen G, Jiang M. Glycoca-
lyx-mimicking nanoparticles for stimulation and polarization of macrophages
via specific interactions. Small 2015;11:4191–200.
[194] Qi W, Zhang Y, Wang J, Tao G, Wu L, Kochovski Z, Gao H, Chen G, Jiang M.
Deprotection-induced morphology transition and immunoactivation of gly-
covesicles: a strategy of smart delivery polymersomes. J Am Chem Soc
2018;140:8851–7.
[195] Pei Z, Dong H, Caraballo R, Ramström O. Synthesis of positional thiol analogs
of β -D-Galactopyranose. Eur J Org Chem 20 07;20 07:4927–34.
[196] Mammen M, Choi S-K, Whitesides GM. Polyvalent interactions in biologi-
cal systems: implications for design and use of multivalent ligands and in-
hibitors. Angew Chem Int Ed 1998;37:2754–94.
T. Pelras and K. Loos
[197] Chen G, Amajjahe S, Stenzel MH. Synthesis of thiol-linked neoglycopolymers
and thermo-responsive glycomicelles as potential drug carrier. Chem Com-
mun 2009:1198–200.
[198] You L, Schlaad H. An easy way to sugar-containing polymer vesicles or glyco-
somes. J Am Chem Soc 2006;128:13336–7.
[199] Schlaad H, You L, Sigel R, Smarsly B, Heydenreich M, Mantion A, Mašić A.
Glycopolymer vesicles with an asymmetric membrane. Chem Commun
2009:1478–80.
[200] Sun J, Schlaad H. Thiol−ene clickable polypeptides. Macromolecules
2010;43:4445–8.
[201] Hu Z, Fan X, Zhang G. Synthesis and characterization of glucose-grafted
biodegradable amphiphilic glycopolymers P(AGE-glucose)-b-PLA. Carbohydr
Polym 2010;79:119–24.
[202] Muñoz-Bonilla A, León O, Cerrada ML, Rodríguez-Hernández J,
Sánchez-Chaves M, Fernández-García M. Glycopolymers obtained by chemical
modification of well-defined block copolymers. J Polym Sci Part A Polym
Chem 2012;50:2565–77.
[203] Scherer M, Kappel C, Mohr N, Fischer K, Heller P, Forst R, Depoix F, Bros M,
Zentel R. Functionalization of active ester-based polymersomes for en-
hanced cell uptake and stimuli-responsive cargo release. Biomacromolecules
2016;17:3305–17.
[204] Tian Z, Wang M, Zhang A-y, Feng Z-g. Preparation and evaluation of novel
amphiphilic glycopeptide block copolymers as carriers for controlled drug re-
lease. Polymer 2008;49:446–54.
[205] Zhang Q, Anastasaki A, Li G-Z, Haddleton AJ, Wilson P, Haddleton DM.
Multiblock sequence-controlled glycopolymers via Cu(0)-LRP following ef-
ficient thiol–halogen, thiol–epoxy and CuAAC reactions. Polym Chem
2014;5:3876–83.
[206] Miki K, Kimura A, Oride K, Kuramochi Y, Matsuoka H, Harada H, Hiraoka M,
Ohe K. High-contrast fluorescence imaging of tumors in vivo using nanopar-
ticles of amphiphilic brush-like copolymers produced by ROMP. Angew Chem
Int Ed 2011;50:6567–70.
[207] Miki K, Oride K, Kimura A, Kuramochi Y, Matsuoka H, Harada H, Hi-
raoka M, Ohe K. Influence of side chain length on fluorescence intensity of
ROMP-based polymeric nanoparticles and their tumor specificity in in-vivo
tumor imaging. Small 2011;7:3536–47.
[208] Aissou K, Pfaff A, Giacomelli C, Travelet C, Müller AHE, Borsali R. Fluores-
cent vesicles consisting of galactose-based amphiphilic copolymers with a
π -conjugated sequence self-assembled in water. Macromol Rapid Commun
2011;32:912–16.
[209] Pati D, Das S, Patil NG, Parekh N, Anjum DH, Dhaware V, Ambade AV, Sen
Gupta S. Tunable nanocarrier morphologies from glycopolypeptide-based am-
phiphilic biocompatible star copolymers and their carbohydrate specific in-
tracellular delivery. Biomacromolecules 2016;17:466–75.
[210] Obata M, Otobuchi R, Kuroyanagi T, Takahashi M, Hirohara S. Synthesis of
amphiphilic block copolymer consisting of glycopolymer and poly(l-lactide)
and preparation of sugar-coated polymer aggregates. J Polym Sci Part A Polym
Chem 2017;55:395–403.
[211] Lipinski T, Kitov PI, Szpacenko A, Paszkiewicz E, Bundle DR. Synthesis and Im-
munogenicity of a glycopolymer conjugate. Bioconjug Chem 2011;22:274–81.
[212] Shi W, Dolai S, Averick S, Fernando SS, Saltos JA, L’Amoreaux W, Baner-
jee P, Raja K. A general methodology toward drug/dye incorporated living
copolymer−protein hybrids: (NIRF Dye-Glucose) Copolymer−Avidin/BSA con-
jugates as prototypes. Bioconjug Chem 2009;20:1595–601.
[213] Shi H, Liu L, Wang X, Li J. Glycopolymer–peptide bioconjugates with antioxi-
dant activity via RAFT polymerization. Polym Chem 2012;3:1182–8.
20
Progress in Polymer Science 117 (2021) 101393
[214] Mancini RJ, Lee J, Maynard HD. Trehalose glycopolymers for stabiliza-
tion of protein conjugates to environmental stressors. J Am Chem Soc
2012;134:8474–9.
[215] Vázquez-Dorbatt V, Tolstyka ZP, Chang C-W, Maynard HD. Synthe-
sis of a pyridyl disulfide end-functionalized glycopolymer for conjuga-
tion to biomolecules and patterning on gold surfaces. Biomacromolecules
2009;10:2207–12.
[216] Liu Y, Lee J, Mansfield KM, Ko JH, Sallam S, Wesdemiotis C, Maynard HD. Tre-
halose glycopolymer enhances both solution stability and pharmacokinetics
of a therapeutic protein. Bioconjug Chem 2017;28:836–45.
[217] Geng J, Mantovani G, Tao L, Nicolas J, Chen G, Wallis R, Mitchell DA, John-
son BRG, Evans SD, Haddleton DM. Site-directed conjugation of “Clicked” gly-
copolymers to form glycoprotein mimics: binding to mammalian lectin and
induction of immunological function. J Am Chem Soc 2007;129:15156–63.
[218] Akasaka T, Matsuura K, Kobayashi K. Transformation from block-type to
graft-type oligonucleotide-glycopolymer conjugates by self-organization with
half-sliding complementary oligonucleotides and their lectin recognition. Bio-
conjug Chem 2001;12:776–85.
[219] Miyata K, Christie RJ, Kataoka K. Polymeric micelles for nano-scale drug de-
livery. React Funct Polym 2011;71:227–34.
[220] Aoi K, Tsutsumiuchi K, Aoki E, Okada M. First synthesis of glycopeptide
macromonomers and graft-type sugar-containing polymers with glycopeptide
side chains. Macromolecules 1996;29:4456–8.
[221] Zhou D, Li C, Hu Y, Zhou H, Chen J, Zhang Z, Guo T. Glycopolymer modifi-
cation on physicochemical and biological properties of poly(l-lysine) for gene
delivery. Int J Biol Macromol 2012;50:965–73.
[222] Serizawa T, Yasunaga S, Akashi M. Synthesis and lectin recognition
of polystyrene core−glycopolymer corona nanospheres. Biomacromolecules
2001;2:469–75.
[223] Beyer VP, Monaco A, Napier R, Yilmaz G, Becer CR. Bottlebrush glycopoly-
mers from 2-oxazolines and acrylamides for targeting dendritic cell-specific
intercellular adhesion Molecule-3-Grabbing Nonintegrin and mannose-bind-
ing lectin. Biomacromolecules 2020;21:2298–308.
[224] Pelras T, Mahon CS, Müllner M. Synthesis and applications of compartmen-
talised molecular polymer brushes. Angew Chem Int Ed 2018;57:6982–94.
[225] Müllner M. Molecular polymer brushes in nanomedicine. Macromol Chem
Phys 2016;217:2209–22.
[226] Müllner M, Müller AHE. Cylindrical polymer brushes – Anisotropic build-
ing blocks, unimolecular templates and particulate nanocarriers. Polymer
2016;98:389–401.
[227] Steinhaus A, Pelras T, Chakroun R, Gröschel AH, Müllner M. Self-assembly
of diblock molecular polymer brushes in the spherical confinement of na-
noemulsion droplets. Macromol Rapid Commun 2018;39:1800177.
[228] Pelras T, Mahon CS, Nonappa Ikkala O, Gröschel AH, Müllner M. Polymer
nanowires with highly precise internal morphology and topography. J Am
Chem Soc 2018;140:12736–40.
[229] Pelras T, Nonappa Mahon CS, Müllner M. Cylindrical Zwitterionic particles via
interpolyelectrolyte complexation on molecular polymer brushes. Macromol
Rapid Commun 2020 press. doi:10.10 02/marc.2020 0 0401.
[230] Adharis A, Loos K. Synthesis of glycomonomers via biocatalytic methods.
Method enzymol. Bruns N, Loos K, editors, Cambridge: Academic Press; 2019.
p. 215–47.
[231] Bernard Julien, Hao Xiaojuan, Davis Thomas P, Barner-Kowolik Christopher,
Stenzel Martina H. Synthesis of Various Glycopolymer Architectures via
RAFT Polymerization: From Block Copolymers to Stars. Biomacromolecules
2006;7:232–8. doi:10.1021/bm0506086.