INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS

https://doi.org/10.1080/00914037.2021.1900181

Glycopolymers in molecular recognition, biomimicking and glycotechnology:

a review
Shatakshi Saxenaa and Balasubramanian Kandasubramanianb
a
Centre for Converging Technologies, University of Rajasthan, Jaipur, India; bDepartment of Metallurgical and Materials Engineering, Defence
Institute of Advanced Technology (DU), Ministry of Defence, Pune, India

ABSTRACT ARTICLE HISTORY

Glycopolymers are multifunctional bio-mimetic supramolecules that can emulate the functions of Received 19 January 2021
glycopeptides. Entitled to molecular recognition, these molecules appertain to amplify the original Accepted 3 March 2021
bio-molecular interactions with lectins. It is ubiquitous that glycopolymers offer the potential to
KEYWORDS
be explored for targeted drug delivery and tumor cell treatment, unfolding new dawn in tissue
Bio-recognition; biodegrad-
engineering. Moreover, their self-assembly trait is advantageous in medical adhesives and ability; glycopolymers;
implants. This review abridges gap, associating physiology of bio-recognition, glyco-polymeric inte- immobilization of
gration, and chemical changes that follow. Techniques for synthesis of these artificial linkers, their glycopolymers; targeted
properties, characterization analysis, and methodologies to improve binding rates and bioactivity drug-delivery; cancer
of glycopolymers are also enlisted. cell therapy

GRAPHICAL ABSTRACT

1. Introduction means of binding with proteins. Considering the trail,

The studies on biological recognition commenced in the
early 1970s; these aimed to unravel the chemical and physio-
logical determinants of molecular interactions to synthesize
artificial bio-mimetic molecules. Meanwhile, the year 1992
witnessed the synthesis of a supramolecule with pendant
carbohydrate units known as glycopolymer. It is discerned
that carbohydrates mediate numerous biological phenomena,
for instance, pathogenic infections or cancer metastasis, via
researchers pursued to fabricate molecules that simulate
similar competency and are efficient in multiple domains
(like drug carriers, antigen-binding agents). Following this
novel invention, intensive exploration of glycopolymers and
their resemblance with saccharides eventuated. The first
report on the administration of glycopolymers for biological
recognition surfaced in the year 2005[1]. All living and
chemical systems harbor distinctive molecular level

CONTACT Balasubramanian Kandasubramanian meetkbs@gmail.com Department of Metallurgical and Materials Engineering, Defence Institute of
Advanced Technology (DU), Ministry of Defence, Pune 411025, India.
ß 2021 Taylor & Francis Group, LLC
2 S. SAXENA AND B. KANDASUBRAMANIAN
recognition. A molecular receptor by virtue of the stored
molecular information selectively binds with a substance;
this interaction results in the genesis of a supramolecular
species[2]. Natural recognition is primarily hinged by the
principle of exploring science involving the riveting of two
molecules. This phenomenon can be explored by delving
into the concepts of biochemistry and host-
guest chemistry[3].
Confabulation on glycopolymers indicates that these are
comprised of monosaccharide/oligosaccharide pendant
groups jeweled to a hydrocarbon backbone[4]. Consequently,
introducing us toward a pilot research field of carbohydrates
coined as glycobiology, which sets forth an insightful under-
standing of the compound chemistry behind saccharide—
receptor interaction. It has unlocked new doors en routing
biomedical applications, like selective and monitored bio-
recognition discretely referred to as Glycotechnology[5, 6].
The anomeric molecule (saccharide polymer) possesses
multiple linkage positions, sub branching as well as variable
ring sizes, these traits confer carbohydrates to be highly dir-
ective in protein binding, and that is why these are multifa-
ceted compared to amino acids or nucleotides. This equips
them to perform glycoprotein like bio-activities and contrib-
ute toward biorecognition. Precision in recognition is of
utmost priority for cell interactions like pathogenic infec-
tions, cell migration, fertilization, embryogenesis, organ gen-
esis, as well as tumor cell metastasis[7–9].
This review advances by enlisting the numerous techni-
ques for the synthesis of these artificial linkers, followed by
a brief disclosure about their properties and characterization
analysis. Studies have discovered that radical polymerization
techniques can expedite the pathway for culturing polymers
with complex sequences. Merging RAFT polymerization
with other click reactions has proven to be felicitous in the
preparation of multiple sequence block and copolymers that
allow a broad spectrum for functionalisation[10]. It can be
said that bio-recognition elements that possess pendant sac-
charides, proudly host a condensed structure that governs
the efficiency of molecular bonding. Therefore it is evident
that controlling the structure of macromolecules is a pre-
requisite to achieve selective saccharide-lectin binding[11].
Glycoproteins just like integrins and cadherins hold the
extracellular matrix and cytoskeleton together, and they
enable cellular interaction with hormones, proteins, toxins
amongst other bio-molecules. Over the decade scientists
have also acknowledged the engagement of glycoproteins in
protein folding and stabilization of the scaffolds, which are
much like the attributes glycopolymers can offer[12].
The microstructural analysis has shown that as lectins
bind with the appropriate saccharide unit, they tend to con-
form into an aggregate, which eventually leads to multiple
ligand linkage[13, 14]. It is noteworthy to mention that sac-
charide receptors are highly selective and are responsible for
the synthesis of glycoproteins[12].
The fifty percent of lectins that are involved in several
vital biochemical reactions are glycosylated and entail the
chemical alterations to be contingent onto sugar code (gly-
copolymer code)[15]. Investigating carbohydrate lectin
interactions lay an invitation for researchers to formulate
methodologies to quantify the degree of binding affinity.
Many have subjugated to turbidity-based testing, wherein
UV-Vis spectrometer was used to analyze the turbidimetric
ratios of proteins to glycopolymers[10, 16].
Researchers have also documented the use of more
advanced processes like ultracentrifugation to evaluated sedi-
mentation velocity that in turn, determines the binding
affinity. In order to understand the association of lectins
and multivalent ligands the benefits of isothermal titration
calorimetry can be employed, followed by the calculation of
various thermodynamic jargons.
The review reports the avant-garde developments con-
cerning glycopolymers and exploration of their molecular
recognition ability, highlighting the physiochemical interac-
tions which lead to binding between the host and guest mol-
ecules (Figure 1). The thorough overview amplifies the
influence that the plasma membrane and its accessories have
on the critical biological phenomenon, for example, anti-
body-antigen interaction or cell adhesion. This paper draws
the audience toward decrypting molecular recognition in a
systematic manner by laying a framework of detailed physi-
ology which highlights host-guest chemistry. All the info-
graphics apprize tales of many significant and revolutionary
trials on glycopolymer application like biodegradable glyco-
polymer synthesis, cancer and immune therapy or drug
delivery strategies. The approach leverages the readers to
acknowledge the importance of devising ways to quantize
and standardize the extent of identification exhibited by the
synthetic alternatives. Furthermore, we have incorporated a
multitude of applications involving glycopolymers and a
reflection of their innate nature to mimic the glycocalyx
environment. The window of molecular recognition exem-
plifies rather than limiting the scope of glycopolymers and
lays stress on answering the loopholes, left in the course of
the afflictions caused due to human interference.
2. Strategies for glycopolymer synthesis
The very recent upsurge toward engaging our focus on the
synthesis of glycopolymers arose apropos the cluster glyco-
sidic effect, as it has been hypothesized that polymers con-
taining pendent saccharide groups because of inherent
multivalency could exhibit advanced biologically relevant
activities as compared to their other alternative counterparts
in the field of medicine. For glycopolymers, it has always
been imperative that synthetic techniques facilitate a narrow
molecular weight distribution and allow maximum control
throughout the process[18]. Glycopolymers are frequently
synthesized using sugar in their pyranose form for the high-
est stability[19]. Protection and deprotection reactions have
influenced the preparation since forever as the cycle moves
clockwise with polymerization of glycopolymer by protecting
groups followed by deprotection, post-polymerization, or it
goes anticlockwise. Ma. Zhiyuan et al. also suggested that by
post-modification of a polymer having a suitable functional
group like thioene, glycopolymer synthesis can be mediated
through click and amidation chemistry. The review reports
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
Figure 1. Various types of molecular recognition events that occur in the homeostasis. Adapted with permission from ref.[17]. Copyright 2019, Royal Society
of Chemistry.
glycodendrimer synthesis as well, and their applications in
the next segment[20–22].
2.1. Ring opening polymerisation
ROMP has always been prevalent among scientists for the
synthesis of glycopolymers as the presence of well-defined
catalysts facilitates polymerization engendering chain specific
polymers having minimal disparities, which is highly desir-
able. Moreover, with the choice of metal alkylidene catalysts,
precise end labels could be introduced aimed for immobil-
ization or detection[23]. ROMP is advantageous as it enables
the use of catalysts that have been fashioned to endure
monomers bearing unprotected polar formalities. This aspect
is crucial as sulfated groups present in biosystems make use
of saccharide determinants, which cannot be easily
masked[24, 25]. Manning et al. performed polymerization in a
mixture of methanol dichromate by the use of triethylam-
monium salts in order to solubilize anionic substrates yield-
ing 3-Sulfogalactose-containing monomers. The reaction
indicated that the termination procedure goes hand in hand,
competing with propagation steps[26]. When the testing was
carried out in water with dodecyl trimethyl ammonium
bromide in stock and with emulsion conditions in play, the
process underwent rapidly consuming the whole monomer.
Their work produced monomers that possessed one sacchar-
ide residue per unit and served as a highly reactive substrate
for ROMP[27, 28]. The increase of reactivity was attributed to
two factors, namely the effect of the electron-rich norbor-
nene derivative and the second being that the strain present
in the bicyclo setting was amplified by fusion of cyclic
amide causing the initiation and initiation rates to rise.
3
2.2. Reversible addition fragmentation chain transfer
polymerization (RAFT)
RAFT enables glycopolymer polymerization with multi block
structures, offering controlled tunability, functionalization
and narrow molecular distribution[12]. Perrier et al. fabri-
cated sequence tailored multiblock glycopolymers by
employing RAFT on polyacrylamides. Their study highlights
the “living” character of this technique, i.e., its ability to syn-
thesize polymer chains which can be extended by adding
monomers even after termination of the reaction[29]. This
characteristic can be explained by the fact that in RAFT, ini-
tiator generated radicals determine number of dead chains
that could be negated due to continuous formation of new
initiators. Similarly, Kichize and group reported the synthe-
sis of multiblock structures with mannose end functionaliza-
tion. Furthermore, they demonstrated molecular recognition
based on lectins and Concanavalin A. The research reveals
specific binding of acrylamide carrying mannose monomer
with Con A, which was evaluated using HI assay
(Hemagglutination inhibition)[30]. The investigation con-
cluded that recognition can be amplified by the multivalent
effect of glycopolymers. These results were obtained due to
optimization of RAFT polymerization. The various types of
end polymers and distinctive features of RAFT polymeriza-
tion are illustrated in Figure 2 along with its developmen-
tal growth.
Quan and team devised a galactose derived thermosensi-
tive nanogel which consisted of a crosslinked core confabu-
lated from di(ethylene glycol) methyl ethyl methacrylate
(DEGMA) cross-linked with N,N0 -methylenebis(acryla-
mide) and a carbohydrate shell consisting of 2-lacto bion
4 S. SAXENA AND B. KANDASUBRAMANIAN
Figure 2. An overview of RAFT polymerization, timeline, types of end polymers and salient features.
amido ethyl methacryl amide and 2-aminoethylmethacryla-
mide hydrochloride[31]. The thermosensitive core induced
collapse of the gel as temperature was raised to 37
C, in
turn prompting drug encapsulation and ASGP-R mediated
uptake succeeded with drug release in hypoxic hepatocellular
carcinoma.
2.3. Atom transfer radical polymerisation
ATRP is preferentially selected to synthesize a variety of
block copolymers by the use of macro initiators like PEG,
PCL, poly (propylene oxide) with the sequential addition of
glyco monomers[32]. Despite its resistance to protein absorp-
tion, nonimmunogenic behavior, low toxicity, and higher
solubility in aqueous mediums, PEG has become a widely
used nonionic polymer[27]. Okada et al. synthesized PEG-b-
poly(2-acryloxyethyl-galactose) via ATRP followed by boro-
nation with poly (3-methacrylamido phenylboronic acid) to
induce crosslinked nanoparticles through the complexation
of cis-diol and phenylboronic acid. These nanoparticles
showed sensitivity to galactose, sucrose, glucose, and man-
nose, while aggregation was observed at ph 5 and 6, whereas
their size increased when the ph was raised to 7 (neutral)[33,
34]
. With the use of sequential ATRP, a PEG polymer for
developing sugar decorated crosslinked micelles having cyst-
amine core, namely PEG-b-poly(2-acryloxyethyl galactose)-
b-poly(acrylic acid) was made for targeted delivery and used
to release Dox inside liver tumor cells[19]. Chen et al. pro-
duced Glycopolymer-polypeptide triblock copolymers by
ring-opening polymerization wherein the monomer
employed L-alanine N-carboxy anhydride was made by
glycopolymer with the use of macro initiators which were
fabricated through ATRP[35].
Another adjoining category of ATRP is Surface-initiated
ATRP. ATRP is an adaptable and multipurpose controlled
polymerization method whose extensive use for polymeriz-
ing brushes by many types of surfaces has led to a plethora
of studies.[36, 37]. Surface-initiated ATRP is a bit different
than ATRP, wherein this straightforward functionalisation of
numerous types of surfaces takes place with the initi-
ator moiety[38].
It is imperative for the successful conduction of ATRP
that a supplementary deactivator is added at the initiation of
the polymerization process[19, 39]. In this manner, there is
an increase in the concentration of inactive or latent species
because of ATRP equilibrium, to increase the deactivator
concentration, the sacrificial initiator comes into action
wherein the solution-initiated polymer chain gets
terminated[40].
Gao et al. argued that as an alternative, the deactivator
could be added directly. The researcher perceived that a
noteworthy difference in the control aspect might be because
of the lack of termination reactions[41]. On the other hand,
the application of the sacrificial initiator has the advantage
that polymer chains are formed in solution, which can sub-
sequently be used for characterization[42]. This is a common
practice since properties such as molar mass, or polydisper-
sity index of solution-initiated polymer chains have been
reported to be comparable to those of the chains growing
from the surface[43, 44].
In this section, the surface-initiated ATRP (SI-ATRP) is
covered only for the preparation of glycopolymers. For a
more improvised overview, the reader is referred to the
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
review article of H.-A. Klok and coworkers on surface-initi-
ated CRP techniques[45].
ATRP has emerged as a promising technique for the syn-
thesis of thermo responsive glyconanoparticles. Otsuka and
group synthesized oligosaccharide based non-linear Diblock
copolymer that function as self-assembled stimuli (tempera-
ture) responsive nanoparticle which were characterized by
scattering and microscopy techniques and were proposed for
sensing applications[46].
2.3.1. Novel glycopolymer topologies using
(RDRP) methods
Reversible Deactivation Radical Polymerization method
includes both ATRP and RAFT technique. This approach
has enabled new horizons to emerge in glycopolymer tech-
nology, allowing ease of functionality and increased range of
application which were restricted in case of linear glycopoly-
mers. Glycodendrimers and bottle brush glycopolymers are
two extensively investigated conformities in the last few
years due to their enhanced affinity toward lectins compared
to linear structures. These can be tailor made with precise
control over grafting density, molecular weight and thick-
ness, and so these are potential game changers in the field
of biomedical science as well as in biomimetics. Bottle brush
glycopolymers express multiple lectin binding sites which
can be drawn for applications in drug delivery systems, can-
cer diagnosis and therapy, super soft elastomers, stimuli
responsive materials and many others. Herein, gold, silicon,
or glass surfaces are functionalized before polymerization
such that the initiating sites can be easily immobilized fol-
lowed by brush growth. Both SI- ATRP and SI- RAFT
methodologies have been explored for preparation of poly-
mer brushes, glucose containing glycobrushes which in turn
show antimicrobial, anti-viral and anti-fouling activity[47].
Li et al. proposed the synthesis of brush glycopolymers
lined with protein anti-adhesive interface embedded on a
gold substrate. The resultant was used to investigate adhe-
sion and anti-adhesion effect of proteins like Con A, BSA
(bovine serum albumin)[48]. The glycopolymer brush was
further scrutinized for colorimetric sensing system which
exhibited instant red shift on addition of PNA, due to for-
mation of cross linkages between glycopolymer and multiva-
lent recognition sites of the tetramer. Another group
employed the concept of thermoresponsive bottle brush like
glycopolymers fabricated via Cu mediated RDRP. The
potential binding with DC-SIGN and its application for
drug delivery was explored. This bottle brush morphology
showed faster binding ability to DC-SIGN compared with
linear glycopolymers indicating independent association and
dissociation constants for different architectures as well as
mutually independent sequence and binding strengths[49]. In
simpler words it can be deduced that binding affinity
increases with increase in monomer valency. The following
figure (Figure 3) encompasses the salient features of glyco-
dendrimers, pointing toward their properties and tunability,
along with a depiction of synthesis technique and its appli-
cation in tumor therapy. It displays how the multifunctional
nanoparticles exhibit imaging and therapy for carcinogenic
5
cells. Jinxia An et al. used targeted drug delivery where
hydrophobic anti-tumor drugs were fabricated through self-
assembly of amphiphilic copolymers via RAFT
polymerization[50].
3. Physiology of biological recognition
Biological activities like adhesion, signaling, differentiation,
cellular level (pathogenic) protection as well as molecular
recognition, are modulated by the information center that
resides at the cellular perimeter known as glycocalyx. Spatial
distribution and morphological glycan framework are
decisive for biological recognition that occurs at the glycoca-
lyx interface[51]. The microstructure has two specific mem-
brane-bound macromolecules, namely glycolipids and
glycoproteins, that are actively involved in the process like
high-avidity responses (antibody-antigen interaction), arbi-
tration of communication between cells[52]. The burgeoning
new discipline involving bio-recognition demands model
systems to explore the science and principles owing to this
phenomenon[53, 54]. It encompasses interactions as precar-
ious as nucleotide base pair matching to immunological
responses; therefore, in order to synthesize artificial mim-
etics understanding the reaction chemistry has pressing
importance. In the aforementioned section, there is a slight
hint at the mechanism involved for these recognition activ-
ities, we discuss it exclusively and elaborately in the follow-
ing section (Figure 4).
Host-guest chemistry is a class of supramolecular chemis-
try comprised of a system of two or more molecules that
bond with each other by interactions apart from complete
covalent bonds, thereby developing exclusive morphological
associations. Endorsing the physiology behind molecular
recognition between antibody-antigens, nucleotide pairs, and
saccharide-lectin interactions it gives substance to the role of
non-covalent bonding in sustaining the stereoscopic struc-
ture of the linker molecules[55]. An analogy to lock and key,
this mechanism upholds the singularity of two molecules in
order to interact; therefore, it outlines the fundamentals of
bio-recognition[56]. Customarily host and guest in biology
were titled as enzyme and substrate. Engineering synthetic
systems that could contrive bio-functions entail us to ingrain
the thermodynamic concepts responsible for binding the
two moieties[57]. Thoma et al. proposed to classify the asso-
ciation of glycodendrimers and drugs (host-guest) as cova-
lent or hydrophobic, respectively, which was later labeled by
researchers wherein the former interaction was considered
as conjugation and the latter as encapsulation. Rising to the
mark molecular recognition is, therefore, a phenomenon of
organization as traced by numerous molecular simulations
and activation constants (Figure 5)[21, 59].
Host or molecular containers possess a cavity to harbor
guest molecules; this mechanism can be employed for
molecular detection, stabilizing excited reactive elements
(bringing them to lower energy state), or even during cataly-
sis reactions[60].
The concept invites us to explore synthetic vessels or host
molecules in terms of stability and preparation; apart from
6 S. SAXENA AND B. KANDASUBRAMANIAN
Figure 3. Glycodendrimers the neo-gen supramolecule and its application in drug delivery.
Figure 4. Various governing principles for biorecognition.
the ease of preparation, they can be fabricated so that they
allow artificial functionalities as well, thereby allowing a
multitude of new properties and applications[61].
Figure 5. Interaction of Glycopolymer with con a, lock and key mechanism.
Adapted with permission from ref.[58]. Copyright 2013, John Wiley and Sons.
In all associations like the role of transcription factors in
DNA recognition or binding of transition states with
enzymes during catalysis, there is a chemical reaction that,
in turn, lowers the activation energy for the transform-
ation[55, 62].
In simpler terms, when we consider thermodynamics, we
cannot overlook entropy and activation constants, thereby
understanding the energy exchange is endorsed to predict
molecular recognition. Moreover, even if we are aware of
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
Figure 6. Role of integrin in cellular recognition.
the bond length, or strength, and even molecular affinity,
the recognition magnitude cannot be wholly estimated.
Pertaining to these loopholes, scientists are still searching
for more minuscule physiological factors responsible for
molecular recognition, i.e., going beyond the first framework
of a guest-host duality. In a recent study, it was also
reported that the pKa values contribute in determining the
affinity toward alkaline ions, directing that these are propor-
tional to binding factors; we figure that entropies too are
rarely observable in single bound structures[53].
In a recent report by Oscar et al., the focus spun around
the placement of epitopes that participate in biorecognition,
quoting that it is the terminal saccharide units out of the
entire glycan cluster which is responsible for saccharide-lec-
tin recognition[63]. While saccharide clusters have a very
similar arrangement compared with water molecules, they
become competitors when present in the binding locale
owing to its hydrophilic properties and the plexus of hydro-
gen bonds[64, 65]. So in order for the host to identify a
carbohydrate, the entropy must be more than the energy
forfeited for degrading receptor shell. To overcome this, the
host-guest interaction bequests on a constructive combin-
ation involving polar binding of the hydrophobic extremities
with the aliphatic saccharide backbone[66]. Furthermore, due
to the single spot distinction between two monosaccharide
units, the task of selectivity gains another stumbling block.
Contriving on the various determinants responsible for
carbohydrate recognition by lectins, we come to an under-
standing that hydrophobic elements that used hydrogen
bonds are typical in most associations. Along with that men-
tions are stating the presence of coordination binding with
hydroxyl moieties of carbohydrates in C-lectins that accent
few calcium ions (Figure 6)[67].
Carbohydrate binding agents or CBA’s acclaim to a hot
field in synthetic recognition research, these can be protein-
based or non-proteic in its lineage. The non-proteic class can
have either covalent or non-covalent linkages when recogni-
tion comes to play. The aforementioned category maneuvers
7
the boronic acid paradigm, consequently building reversible
bonds with ortho and meta diolic sets[68]. Within the human
body, when we associate glycoproteins with antigen recogni-
tion units, T cells emerge in the concept.
The T-cell receptor extends as a heterodimer of glycopro-
tein accommodating, the cell surface, which combines with
the CD3 marker to complete the antigen recognition unit.
TCR is composed of either one of the two glycoprotein
chains videlicet ab or cb where ab is carried in the majority.
TCR belongs to the immunoglobulin gene superfamily
expressing four separately encoded regions- variable, diversity,
Joining, and constant, which on reassortment give rise to an
extensive repertoire of protein-specific recognition. Integrins
have been explored by research groups over the past decade
to establish an understanding of cellular adhesion[69].
4. Quantifying the degree of biological recognition
It is an irrefutable verity that all chemical conversions
involve some degree of energy exchange. Now to delve to
the crux of these recognition associations, scientists are
orchestrating ways to quantify these interactions and stand-
ardize a way to mark the efficiency of synthetic linkers.
They have employed many techniques such as NMR spec-
troscopy, UV/visible spectroscopy, isothermal titration calor-
imetry, quantitative analysis for binding constant values to
list a few[70]. Merging their results yields efficacious thermo-
dynamic figures.
It has been relayed over the last decades that the binding
affinities of saccharide-lectin interaction amble in millimolar
to micromolar scale; it is therefore considerably weak com-
pared with protein-ligand dyad[71, 72].C. Wang et al. pro-
posed that Atomic force microscopy-based spectroscopy
could be employed as a tool for the investigation of molecu-
lar and submolecular processes. If molecules manifesting
discrete interaction be immobilized using covalent bonds on
the substrate over an AFM tip, there can be a breakthrough
in computing interaction forces at pico Newton
8 S. SAXENA AND B. KANDASUBRAMANIAN
Figure 7. A pH-responsive block glycopolymer.
resolution[73]. If we resolve the difference in interaction
forces between antibody-antigen recognition processes
amongst natural and artificial mimetics at the minuscule
ensemble, then the fabrication of evolved recognition units
can be accelerated[74]. They propounded on utilizing plas-
monic nano transducers that allow modulation of bioconju-
gation and imprinting processes at the nanoscale with
hemoglobin as the protein target[75]. Now, to ascertain the
energy and kinetics determinants along with dissociation
rates and changes in energy barriers Wang et al. tried vary-
ing the load rates at the tip following the principle of
Dynamic Force spectroscopy[76]. Furthermore, they have
considered refractive index sensitivity of plasmon resonance
wavelength to explore the biosensing abilities of the recogni-
tion units and tallied it with the subsequent dissociation and
DG values[70]. Zhiyuan Ma et al. established that variation in
the structure of the aggregate correspond to different
degrees of peptide-lectin association or binding. They vali-
dated this by synthesizing a pH-responsive Diblock glyco-
polymer which could be used as drug delivery vehicles with
stimuli sensitive release, Figure 7 illustrates the process[19].
Saccharides have abilities to undertake selective binding
with proteins; this can be reinstated by investigating Con A,
a lectin (carbohydrate-binding protein) originally extracted
from jack-bean, or Canavalia ensiformis. Con A has drawn
attention over the past few years because it can distinctly
recognize pyranoside residues complemented with hydroxyl
moieties besides that crosslinked aggregates of Con A are
formed when it binds with glycopolymers[77–79].
Pie et al. employed UV-Vis spectroscopy, DLS, TEM to
explore the attributes of specific recognition by allowing
in vitro interaction of Con A and glycopolymers modified
gold nanoparticles at room temperature[80, 81]. Their obser-
vation reckoned substantially on the shift seen in the UV
spectrum with bovine serum albumin set as the control,
and, the experiment was carried by altering the volumes of
Con A. It needs to be noted that the inclusion of BSA did
not tweak the maxima of LSPR band nor did it unveil any
cluster or aggregate in the microstructure analysis[82].
Meanwhile, as the concentration of Con A increased, the
spectrum revealed a bathochromic shift from 520 nm to
555 nm, depicting the concoction of crosslinked aggregates.
Additionally, with the increase in the concentration of
ConA, there was a significant escalation in particle radii
whereas the DLS results showed no such change on the add-
ition of BSA solution. Later the TEM analysis demonstrated
that there were no more unreacted glycopolymers gold spe-
cies. Instead, the team witnessed the presence of ameboid
aggregates between Con A and glyco gold nanoparticles[83].
With the report thereof, we can estimate that the earlier
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
Figure 8. Microcontact printing and fluorescence imaging applied to investigate binding efficiency.
tests confirmed a targeted recognition, which was followed
by a very lucid image of binding between the individual
units, so it can be proposed that targeted delivery and thera-
peutics are plausible applications thereof.
In search of a way to quantify the extent of selective
binding, research groups have also developed glycopolymer
libraries and wielded them for high-end testing of carbohy-
drate protein association. Some have also suggested that
optical measures could be rewarding for precise and sensi-
tive screening[44, 84]. With that in mind, the literature
acclaims that surface plasmon resonance imaging is an adept
technique to scan prodigious libraries that works efficiently,
even without labeling proteins[85, 86]. The Yuri group-
administered glycopolymers to recognize Cholera Toxin B
and galactose units and examined them under SPRI for the
variation in the proportion of carbohydrate and hydropho-
bic units[87, 88]. As we discussed earlier that all energy con-
versions require activation constant; similarly, they also have
a requisite for binding factors. On that account, Kimoto
et al. evaluated the binding constant values from the screen-
ing data. The nonlinear regression approach befitted their
drive of obtaining binding constants[89, 90]. So the SPRI sig-
nal curves were calibrated for all protein concentrations, and
the plot was analyzed thereafter using the equation here-
under.
Ka  cDRmax
DR ¼ , (1)
1 þ Ka c
9
where R is the SPRI signal, Ka being the binding constant,
and c indicates the protein concentration. The results lastly
indicated that glycopolymers that embody ultra-hydrophobic
monomeric units exhibit high values of binding
constants[91].
Researchers have also turned toward quenching and
fluorescence quenching as another option to determine the
degree of association[92–94]. In a neoteric report, a group
chose to undertake fluorescence quenching experiments with
substrates like galactose recognition lectins, di, and triblock
copolymer, among others, to observe which induce fluores-
cence changes. For instance, both peanut agglutinin (galact-
ose recognition protein) and Con A with TEG did not
influence the fluorescence band (DF). Although Jono et al.
published an issue claiming that the bonding of mannose
ligand with Con A accorded toward fluorescence quench-
ing[88]. Alike Pie et al. also estimated polymer size using the
DLS principle, which later confirmed that the individual
radii were less than 10 nm, concluding that they were pre-
sent in a monomeric state[95].
The analysis demands a way to control the molecular
length because to amplify multivalent interaction, glycopoly-
mer induced recognition needs to be manipulated by ideat-
ing the assembly of single polymer (micelle)[96]. Another
study employed a micropattern binding lactose with seques-
tered Psophocarpus tetragonolobus labeling with isothiocy-
nate[97]. Figure 8 shows how the glycopolymer patterned
sites demonstrate lectin binding while the rest of the PET
surface lacked fluorescence.
10 S. SAXENA AND B. KANDASUBRAMANIAN
Figure 9. Fabrication of receptor mimics for anti-tumor cell therapy. Adapted with permission from ref.[17]. Copyright 2019 Royal Society of Chemistry.
With an appetite to achieve that, Jono and the group
proffered onto molecular modeling, thereby evaluating the
polymer size using the Monte Carlo equation[98]. The find-
ings thus obtained implied that if the length of the carbohy-
drate-binding site in Con A is greater than 6.5 nm coupled
with the presence of saccharide block at both extremities,
then the molecule shows increased binding affinity, authen-
ticated by a significant rise in Ka value[88].
5. Applications
Biomimetics is a field that embraces imitation of biotic sys-
tems and elements with the motive of building technology
that can elevate humankind. The oligosaccharides located in
the human body boast versatility in isomer genesis, which
arises from their ability of high-density coding[99]. This line
of logic has a knack to be further implemented toward syn-
thesizing natural superstructures. Glycopolymers have a his-
tory of being thoroughly probed in innumerable and diverse
fields like sensing, separation science, catalysis, as a synthetic
biomaterial for therapeutics, or catalytic reactors for chem-
ical synthesis, as well as targeted delivery vehicles for drugs
with enhanced contrast imaging to list a few[100]. The paper
reviews various domains that employ glycopolymers as suc-
cessful substitutes for other natural or artificial elements and
highlights the accomplishments of administering the supra-
molecule in the thriving sector of molecular recognition.
Glycopolymer Technology has spruced up with the
expansion in the field of nanotechnology that ingrains the
quality of self-assembly and sophisticated transplant[50, 101].
Although saccharides in their monomer form cannot skite
about strong binding, this triviality can be conquered by
inducing multivalency[102].
5.1. Biosensors and catalytic reactors
Plasmonic nanoparticles have been in loud whispers in
recent years, these particles range between 1 and 100 nm
and have a characteristic of exhibiting collective oscillations
when the light of specific wavelength is incident on them.
This plasmon resonance effect can impact the chemical
activity pertaining to their inflated stability and ease of func-
tionality. Surface functionality thereby endows enhanced col-
loidal permanence as opposed to reduced cellular toxicity, so
glycopolymers coated with plasmonic nanoparticles are
promising as food additives that can be readily disposed of
the body[61]. Interestingly glycopolymers-based nanoparticles
can coherently generate large magnitude electromagnetic
fields at the molecular surface; this can be further employed
to multifold the scattering response of adjacent particles[103].
This phenomenon is coined as Surface enhanced Raman
scattering (SERS), with its unique ability to detect even an
isolated molecule scattering (SERS), SERS has metamor-
phosed the idea of biosensing[104].
These containers do not appeal with host-guest system-
atics lacking the ability to encapsulate biomolecules; hence
post-polymerization transformations can be of assistance to
revise these into stable supramolecular assemblies with high
specificity in host-guest dynamics[105]. They are not only sta-
ble but also have sticking preparation methodologies, along
with the fact that these can be recycled and are way
cost-effective as compared to natural substitutes. Thereby
complementing their grounds as more promising sensor
devices[106]. Another example setup by Qi Liu and team
micro designed cancer cell membrane adapted with pMAG
and pMAM glycopolymers that insist on selective binding
for different receptors[107]. Figure 9 depicts how this inter-
action stimulates an anti tumor immune response.
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
Figure 10. Synthesis of Insulin mimic and its administration pathway.
In order to customize glycopolymer-based plasmonic
nanoparticles, scientists have dived into the microstructural
arrangement, claiming that the molecules possess a size
comparable with guest molecules.
It facilitates them to detect particles that are hard by the
plasmonic surface; the structure can be further fine-tuned to
design synthetic containers with affinity and selectivity simi-
lar to biomolecules[107, 108]. Moreover, self-assembled glyco-
polymers containing gold nanoparticles have also shown
applicability as catalytic reactors used for chemical synthesis
together with vehicles for targeted drug delivery and impro-
vised contrast imaging[109].
5.2. Molecular recognition abilities
The literature quotes that bio-recognition elements that pos-
sess pendant saccharides host a condensed structure that
governs the efficiency of molecular bonding. Therefore it is
evident that controlling the structure of macromolecules is a
pre-requisite to achieve selective saccharide-lectin bind-
ing[110]. Many have scoured through the various synthesis
methodologies and tried experimenting with the surface
phenomenon to achieve artificial molecular recognition
using glycopolymers and have attained high altitudes, by
addressing hurdles like cancer, or neurodegenerative disor-
ders, the inability of blood coagulation, to bacterial and viral
toxins, and have also embarked onto targeted delivery.
11
5.2.1. Targeted drug delivery
Pie et al. reported that amphiphilic glycopolymers could be
reconstructed using gold nanoparticles, which would actuate
self-assembly in the hybrid nanostructures, thereby building
multifunctional containers (like micelles) environing the sac-
charide unit[111].
With the inclination to synthesize well-defined biomim-
etic supramolecules, Pie and the group followed the litera-
ture to create chemically inert gold nanoparticles with an
enclosed glycopolymer chain[112]. The line of action was sta-
bilization with some dimer followed by dissolving the entire
compound in DMF and dialyzing it for another 72 hours.
The procedure was crucial in the vision of controlling the
molecular weight distribution[113]. The latter was analyzed
using gel permeation chromatography that hyperbolized
symmetrical and single-mode peaks defining the existence of
distinct glycopolymer entities. As a result of mushrooming
hydrophobic interaction, the distance between individual
molecules decreased whereas the overall chain length
increased, additionally the irregular ameboid clusters trans-
formed into compact spherical aggregates.
This turn of events gives us a primary overview that
hydrophobic interactions are imperative for self-assembly,
which is analogous with the hydrophobic property of glyco-
peptides in the cellular environment[7]. Hence, the inter-
action of glycopolymers with gold nanoparticles can pave a
way toward targeted biological applications and also photo-
thermal therapy[114]. Targeted drug delivery has been
12 S. SAXENA AND B. KANDASUBRAMANIAN
Figure 11. An Artificial heparin mimics with glycopolymer and inducing blood coagulation in hemophilic patients.
employed to explore various setups, like insulin delivery and
vaccination[115].
Figure 10 is a pictographic representation of research
undertaken by the Shi group, reporting fabrication of glu-
cose responsive micelles[116]. Insulin release in the case was
achieved by the switching of glycosylase molecule by glu-
cose, resulting in self-regulated insulin delivery. Recently
Ozgen et al. have introduced a novel approach of integrating
glycoblock polymers on a multiwalled carbon nano tube, for
effective stimuli-induced drug release in breast cancer diag-
nosis and therapy. The preparation of doxorubicin and gly-
coblock copolymer conjugates has been reported which was
later loaded by non-covalent attachment on CNTs. The thus
prepared conjugate showed heightened anticancer efficacy
due to improved cellular uptake[117].
5.2.2. Cancer therapy
In contrast, Haddleton et al. fabricated a medley of glycopol-
ymers through the ATRP technique with pendant groups
like galactose, lactose, or mannose sugars. Binding of
Ricinus agglutinin protein was observed with the initial two
sugar moieties, whereas mannose with a glycopolymer back-
bone was exploited for binding affinity toward Con A.
Glycoconjugates were analyzed using ELISA, and they were
successful in activating the recognition system.
Glycopolymers bearing lactose and mannose moieties also
demonstrated affinity with other biotic elements (plant and
animal proteins)[118]. With the potency of targeting cancer
cells, many such glycopolymer conjugates have been fabri-
cated over the years, for example, CPMV-glycopolymer.
Spain and coworkers coated plant protein over agarose
beads, which consequently exhibited aggregation, thereby
depicting carbohydrate lectin binding[119]. These mimics can
work miracles in a myriad of biorecognition processes, that
require specific binding or can also act as competitors in the
host-guest mechanism. Li and coworkers studied the
expression of glucose transporters and their proliferative
regulation in tumor cells. Hela cell line (an immortal cell
line derived from the cervical cells) was used for the follow-
ing analysis to determine the chemical affinity and cellular
intake of glycopolymer coated with iron oxide nanoparticles
with tumor tissue (Figure 11)[119, 120].
This marked a flair toward imaging and bio labeling
applications. The follow-up for the study was such that Li
et al. incubated HeLa cells with Rhodamine tagged glycopol-
ymer based iron oxide nanoparticles for 6 hours and studied
the captured cells thereof, via a confocal microscope. The
conjugate is supposed to accumulate at the cell membrane
of HeLa cells, indicating improvised binding efficiency. This
was reaffirmed through intense fluorescence signals from the
circumference of HeLa cells[121]. To further analyze the cyto-
toxicity of iron oxide coated glycopolymers, the uptake of
nanoparticles per cell was evaluated using the following
equation (p ¼ density of iron oxide nanoparticles, w ¼ mass
fraction of iron in Ferric oxide).
CV=w
N¼ =U (2)
Dp
They have also included the effect of cellular shape in the
degree of uptake, quoting that the aspect ratio influences the
absorption[42]. Henceforth cubical nanoparticles have a
greater likelihood of invading a cell as opposed to spindle-
shaped molecules[115].
5.2.3. Combating acquired immunodeficiency syn-
drome (AIDS)
Researchers have turned toward glycopolymer compounds
as an aid to combat immuno deficiency syndromes. In order
to fabricate a glycopolymer that can mimic the receptor that
encrusts viral DNA/RNA and allows it to proliferate let us
first understand the defence mechanism of our body against
such infiltrators. A lectin receptor abbreviated as DC-SIGN
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
Figure 12. A breakthrough fabrication of Biodegradable glycopolymer with specific binding properties. Adapted with permission from ref.[127]. Copyright 2016,
American Chemical Society.
is located on the surface of dendrites and macrophages in
the body, it recognizes and binds with a specific family of
pathogens, and this interaction induces phagocytosis[122].
Through multiple trials, scientists have come to a break-
through that glycopolymers with mannose pendant units
have an affinity for DC-SIGN and can obturate the inter-
activity between HIV envelope glycoprotein and DC-
SIGN[44, 123].
Becer et al. placed their reliance on the theory of devel-
oping glycopoymer libraries by virtue of Copper dependent
radical polymerization as per the Huisgen cycloaddition
reaction. They examined the degree of binding between the
glycopolymers and tetramers of DC-SIGN protein (recom-
binant bacterial strain) plying with Surface Plasmon
Resonance[124].
As the glycopolymer concentration fluctuated, the bind-
ing interactions between the immobilized lectin on the sen-
sor tip and the fabricated supramolecule were reported. To
the surprise it was observed that the copolymer with pen-
dant mannose had the maximum affinity with DC-SIGN
when put together with the HIV glycoprotein. It is needless
to mention that establishing self-complementarity among
molecules has led research brains into a swampy terrain, but
with the resurfacing of mannose containing glycopolymers,
there is a ray of hope. Anti-adhesion therapy relies on the
potential of artificial spinoffs to interrupt pathogenic (viral)
binding to the host.
The competition assay orchestrated to estimate the drug
potency revealed that as the amount of mannose sugar
quadrupled, the value of half-maximal inhibitory concentra-
tion (i.e., the concentration of a drug that is required for
50% inhibition in vitro) nosedived from 1,453 M to 37109
M. This demonstration validated the assertion proving that
13
the neo fabricated polymer can be used to curb HIV capsid
binding with human macrophages.
5.2.4. Take on neurodegenerative disease
Yoshika’s study apropos of fabricating a polymer look-alike
of glycosaminoglycan as a mimic polymer for Alzheimer’s
amyloid b inhibitor. The paper reports the synthesis and
polymerization of a chief component of glycosaminoglycan,
namely vinyl saccharide[125]. The study probed the imitation
of heparin with b amyloid ab (here ab comprises of 39–43
amino acids), the latter being a pathogen for Alzheimer’s.
Glycosaminoglycan (heparin) binds with this small peptide
(ab); meanwhile, ab is known to develop clusters that trans-
form into fibrils and cause cellular toxicity[118]. The research
implied that sulfonated glycopolymers with minimal carbo-
hydrate fraction stifle the generation of amyloid fibrils,
thereby lowering the cytotoxicity of ab protein. These tests
were also carried out by employing identical monomeric
saccharides, but the results were far-flung, suggesting that
multivalent glycopolymers were crucial for amyloid inhib-
ition. Therefore, it can be undoubtedly formulated that the
artificial supramolecule not only constrains the protein syn-
thesis but also causes conformational alterations in the mol-
ecule, gradually changing it to a much spherical form[126].
Bio-degradability is the demand of the hour, and if we could
develop such delivery vehicles and containers, glycopolymers
would become a sustainable boon for the research commu-
nity. Silvia Ganda et al reported the synthesis of a bio-
degradable drug delivery platform attributed by control of
radical ring-opening polymerization employing RAFT tuned
to attain a higher degree employing enzymatic attack in a
less time for main chain scission. A systematic
14 S. SAXENA AND B. KANDASUBRAMANIAN
Figure 13. Physiology of cellular adhesion to understand the fabrication requisites for integrin mimic.
representation of the synthesis procedure involved is shown
in Figure 12. The research group finely regulated the ratio
of BMDO incorporation to achieve distinct degree of ester
cleavage bonds. An interesting factor of the study was that
dry and inert atmosphere was used for synthesizing BDMO
monomer via reduction reaction as the monomer is highly
susceptible toward hydrolysis. Moreover, a sequence of
copolymerization reactions were performed by varied co-
monomer feed ratios in order to analyze the versatile nature
of copolymerization for control of rROP. The resultant gly-
copolymer can be used as a vehicle for treatment of diseases
that require the drug to cross the blood brain barrier and
this polymer shows high degree of biocompatibility and
non-toxicity of degradation products, established via in vitro
cell proliferation assay against healthy human fibro-
blast (HS27).
5.3. Cellular adhesion
This review integrates the theories and observations of
research groups that have employed the biorecognition abil-
ity of glycopolymers for cellular adhesion and further appli-
cations. Glycopolymers have demonstrated several potential
functionalities as tissue adhesives or pressure-sensitive adhe-
sives coming from their elastomeric tendency[128].
Pramudaya et al. amalgamated a glycopolymer (Poly MG)
interpenetrated with collagen, which resulted in the develop-
ment of hydrogel. The preparation of hydrogel was followed
by polymerization and crosslinking with polyethene glycol.
The polymer, when tested for mechanical properties,
revealed a similar trend with that of the human cornea[129].
Further testing for the binding compatibility verified the
synthetic product, as the epithelial cell count of cornea
favored this hydrogel over collagen[130]. Papers have also
reported that it has anti-adhesive properties for bacterial cell
membranes. Another study shipped about heavy glycopro-
teins such as mucin and the degree of access mucin mim-
etics can allow probing the nanoscale properties of the
glycocalyx[131]. A very recent investigation by Bertozzi et al.
highlighted the influence of mechanical forces exercised due
to mucin glycocalyx that directs integrin protein toward
focal adhesion, which is of crucial significance for cell prolif-
eration and ligand binding[132]. They employed the mucin
mimetic glycopolymer to fashion mammary epithelial cells
and studied integrin aggregation[133]. The mention also cited
that the length of the polymer was a deciding factor to
induce clustering, cell adherence and multiplication.
Considering the fact that mucins are involved in intracellu-
lar signaling and have been reported to multiply in most
types of tumors, the group has engineered several chimeric
membrane proteins enclosing mucin mimetics in order to
increase the efficacy of glycopolymers technology.
The following figure represents the physiological basis of
cell adhesion; this is important for curating novel mimics
(Figure 13).
Porphyrins are organic chromophores with flexible pho-
tophysical attributes. It appeals to the scientific community
because of its compatibility with cancer imaging and photo-
therapy[35, 134, 135]. The only bottleneck in its applicational
success is its hydrophobicity and skin phototoxicity. In
order to cut the Gordian knot, researchers have tried to
modify porphyrins using glycopolymeric coats. This not
only minimized the toxic potency but has enhanced its affin-
ity for lectin receptors.
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
Figure 14. Diblock glycopolymer for MRI and chemotherapy.
5.4. Imaging and tissue engineering
Supramagnetic iron oxide nanoparticles have emerged as
exceptional materials for imaging applications like MRI or
magnetic force drug delivery. These can be revolutionized
by encrusting them with glycopolymeric units that afford
them with biocompatibility[136].
5.4.1. Microstructural imaging
In a literature report, Li and coworkers have synthesized
glycopolymers embedded inside an iron oxide core and ana-
lyzed its absorption trail[137]. To establish that the polymeric
nanoparticle was stable and resized all nonspecific binding,
the group allowed it to disperse in BSA þ PBS buffer solu-
tion, which revealed no alteration in nanoparticle size. The
experiment continued with an evaluation of the interaction
between glycopolymer nanoparticle and Con A. The prin-
ciple of increase in particle size due to conjugation overtime
was implemented to calculate the extent of bioactivity using
DLS guidelines[138, 139]. The hypothesis was confirmed as
the particle size grew persistently with increased binding
and crosslinking. Ning Li and others proposed the develop-
ment of reduction sensitive linear glycopolymers which
specified unique recognition and binding abilities with wheat
lectin. Furthermore, the molecule was employed as theranos-
tic nano-carriers for imaging applications (Figure 14)[140].
El-Boubbou et al. synthesized magnetic (responsive)
glyco-nanoparticles functionalized with monosaccharides to
operate as nanosensors. These MGNPs respond to magnetic
15
field and can be used to map out tumor-carbohydrate inter-
action using MRI signature. The data obtained from MRI
allows differentiation between isogenic sublines in tumor
cells, even metastatic cells can be identified using MGNPs,
secondly this data can be employed for the fabrication of
antiadhesive agents[141]. A recent scientific propensity
toward quantitative H2O2 monitoring has surfaced, because
if the fact that excessive increase in its amount may stir oxi-
dative stress or stimulate tumors and neurodegeneration.
Fluorescent glycopolymers open a window for the detection
of cytosolic H2O2 pertaining to their non-cytotoxic nature
even at high concentrations. Zhang et al. have reported
MTT assays that confirm biocompatibility show-
ing maximum
Reduction in cell viability by 5%. They used glycopoly-
mers as fluorescent probes to locate mitochondria, this
property is due to their high grafting ratio which corre-
sponds to high sensitivity, stability and selectivity. Outcomes
of confocal fluorescence imaging show successful incorpor-
ation of fluorescent glycopolymers in mitochondrial bodies,
this stems from the fact that the availability of H2O2 is
mainly in these energy organelles[142].
5.4.2. Tissue engineering
Zhiyuan et al. scrutinized the applications of saccharides in
hard tissue engineering that led to the fabrication of cartil-
age, teeth, bone, etc.[143]. Tissue engineering strategies have
been vividly covered in the review by Rastogi et al. with an
insight into acclimatizing 3 D/4D printing and smart
16 S. SAXENA AND B. KANDASUBRAMANIAN
Figure 15. Glycopolymer mimic for E coli. lectin.
materials with applications in the biomedical domain[144].
Alongside research groups have also investigated hydrogels
based on glycopolymers with pendant mannose sugar, dis-
playing exceptional cyto complementarity and are promising
approaches for 3 D scaffolds[19]. Dendritic glycopolymers
combined with cellulose sulfate are registered as effective
composites for the treatment of osteolytic bones. In a study
related to the development of dental carries, glycopolymers
were probed to sequentially bind with the most harrowing
pathogen responsible for oral carries[145]. The glycopolymer
has been inquired for anti-adhesion mechanism; thereby, it
can regulate the oral infection.
5.5. Glyco-nanomedicine
It can be irrevocably said that multivalency exaggerated the
binding affinity in glycopolymers. Antibodies or glycopro-
teins induce inhibition in pathogenic lectins like CTB or
ricin if they enter the human body. To implement this the-
ory, Yan et al. decided to marry E. Coli bacteria to glycopol-
ymers embedded with nanoparticles. Although bacteria are
incapable of self-clustering in the aqueous medium, they
clump onto the glycopolymers as a repercussion of the asso-
ciation of pendant mannose with the bacterial cell mem-
brane[146]. The investigation soared in averting and
obliterating the ever-burgeoning population of E. coli even
at minimal glycopolymeric concentration.
Cai et al. have reported the fabrication of a branched gly-
copolymer conjugated with a chemotherapeutic drug with
fluorescent probe pheophrobide for applications in theranos-
tic nanomedicine. The prodrug shows stimuli-induced
release and enzyme responsive degradation. The drug shows
longer blood half time, bright MRI contrast, improved anti-
cancer efficacy and is reported to inhibit progression of 4T1
xenograft[147].
Research has surfaced in the last years where RAFT poly-
merization was employed to fabricate star topology of glyco-
polymers for tailoring and inhibiting binding with influenza
virus. Yoshiko Miura and group investigated the interaction
of 60 -siallyllactose functionalized glycopolymer with virus
using HI assay. Hitherto, the glycoprotein feutin was identi-
fied because it can inhibit the aggregation of red blood cells
which is a result of the viral infection[148]. The study showed
the absence of nonspecific interaction between spacer
 INTERNATIONAL JOURNAL OF POLYMERIC MATERIALS AND POLYMERIC BIOMATERIALS
segment of SD45 while the interaction of SD24G10 was
reported to be stronger with HA than feutin, implying that
biomimics can be superior viral inhibiors. Also, these star
shaped glycopolymers do not inhibit RBC aggregation indi-
cating highly selective association with glycounits
(Figure 15).
6. Future prospects and conclusion
The scientific community has been blatantly exposed to the
inundating rise in the development of exclusively tailored
medicines, discrete to individuals or selected groups of
patients. This proposition elevates the efficacy of the admin-
istered drug and thereby avoids all possible redundancies.
Biomimetic technology is a cutting edge genre of medical
engineering in the present-day world. The brief enclosure
about glycodendrimers is, in itself, a ground-breaking
example of the beginning of an era of nano vaccines and
drug delivery systems based on glycopolymers.
Another undefied zone belongs to bulk tissue adhesion
engineering, whose depths are waiting to be plumbed
between the split potential where glycopolymers proffer
impressive aqueous stability, hydrogel like flexibility, and
expansive resourcefulness for biorecognition. The fruits of
nanotechnology can be reaped to escalate antigenic delivery,
vaccine/drug formulation as much as nano toxoid synthesis,
thus imparting ailment specific immunity. To add to it,
there is an impending demand for co-delivery of immunos-
timulatory adjuvants with antigenic drugs, which can be
addressed by enclosing either one inside a nanoparticle and
coating the remaining one over it. The exponential develop-
ment in glycopolymer technology might be a way to address
the elephant in the room, i.e., “COVID-19.” The probability
of fabricating a competitive mimic, just like those for anti-
adhesive therapies, in this case, is unquestionably high.
This review turns out to be a cumulative analogy of gly-
copolymer technology. Traversing smoothly from fabrication
strategies to coalescing all factors and elements associated
with biorecognition, it earmarks as a concrete source of
information on supramolecular chemistry. It secures the
multiple ways in which molecular affinity can be investi-
gated and provides a detailed account of implementing
chromatography, spectroscopy, and imaging techniques for
the same. Ultimately the paper takes account of how glyco-
polymers have been employed in biomimetic applications
and appraises the interaction of the synthetic molecule with
the human body.
Acknowledgments
The authors would like to thank Dr. C. P. Ramanarayanan, Vice-
Chancellor of DIAT (DU), Pune for the support. The authors thank
Mr Prakash Gore for the technical help due the course. The first
author dedicates this paper to her grandfather Mr. Mukut Saxena. The
first author also thanks her parents, Dr. Ashish Saxena and Dr. Pinku
Sinha, for sharing their views on the physiology of recognition and
suggesting reference literature. The first author acknowledges her
brother Mr. Nipun Saxena for his inputs in designing the paper layout.
17
ORCID
Balasubramanian Kandasubramanian http://orcid.org/0000-0003-
4257-8807
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