Current-status and applications of polysaccharides in drug delivery systems

Prasher, P., Sharma, M., Mehta, M., Satija, S., Aljabali, A. A., Tambuwala, M. M., Anand, K., Sharma, N.,
Dureja, H., Jha, N. K., Gupta, G., Gulati, M., Singh, S. K., Chellappan, D. K., Paudel, K. R., Hansbro, P. M., &
Dua, K. (2021). Current-status and applications of polysaccharides in drug delivery systems. Colloid and
Interface Science Communications, 42, 1-17. [100418]. https://doi.org/10.1016/j.colcom.2021.100418

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Published in:
Colloid and Interface Science Communications

Publication Status:
Published (in print/issue): 31/05/2021

DOI:
10.1016/j.colcom.2021.100418

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Download date: 22/12/2022

Highlights

Highlights

This review article presents:

1. Nature of polysaccharide-drug interactions

2. Factors influencing the drug delivery by polysaccharides

3. Advanced drug delivery applications of polysaccharides

Graphical Abstract

TOC Graphical Abstract

Title Page (with Author Details)

Current-status and applications of polysaccharides in drug delivery

systems

Parteek Prasher1*, Mousmee Sharma2, Meenu Mehta3, Saurabh Satija3, 4, Alaa A. Aljabali5,
Murtaza M. Tambuwala6, Krishnan Anand7, Nitin Sharma8, Harish Dureja9, Niraj Kumar Jha10,
Gaurav Gupta11, Monica Gulati12, Sachin Kumar Singh12, Dinesh K. Chellappan13, Keshav
Paudel14, 15, Philip M. Hansbro14, 15, Kamal Dua3, 14*
1. Department of Chemistry, University of Petroleum & Energy Studies, Dehradun
248007, India
2. Department of Chemistry, Uttaranchal University, Dehradun 248007, India
3. Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney,
NSW 2007, Australia.
4. School of Pharmaceutical Sciences, Lovely Professional University, Phagwara,
144411, Punjab, India
5. Yarmouk University, Faculty of Pharmacy, Department of Pharmaceutics and
Pharmaceutical Technology, Irbid 566, Jordan
6. School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine, County
Londonderry, Northern Ireland BT52 1SA, United Kingdom
7. Department of Chemical Pathology, School of Pathology, Faculty of Health Sciences
and National Health Laboratory Service, University of the Free State, Bloemfontein,
South Africa
8. Department of Pharmacy, Merrut Institute of Engineering and Technology 250005, UP,
India.
9. Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak
124001, India.
10. Department of Biotechnology, School of Engineering and Technology (SET), Sharda
University, Greater Noida, 201310, UP, India.
11. School of Pharmacy, Suresh Gyan Vihar University, Jaipur, Rajasthan, India
12. School of Pharmaceutical sciences, Lovely Professional University, Jalandhar-Delhi
G.T Road, Phagwara, Punjab, India
13. Department of Life Sciences, School of Pharmacy, International Medical University,
Bukit Jalil 57000, Kuala Lumpur, Malaysia
14. Centre for Inflammation, Centenary Institute, Sydney, NSW, 2050, Australia
 15. School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo,
NSW, 2007, Australia
*Corresponding author email: [email protected], [email protected]
Revised Manuscript (Text Unmarked) Click here to view linked References

Keywords: Polysaccharides, Drug delivery, Biocompatible.

Abstract
The polysaccharide-based advanced drug delivery system owing to their biocompatibility, ability
to encapsulate the drug molecules in their interspaces, and ability to achieve a controlled release
of the cargo drug molecules result in improved drug pharmacokinetics. The drug-loaded
polysaccharides possess ability to evade the multidrug-resistant microbial efflux pumps by
aggregation effect, whereas the drug loaded polysaccharide-fabricated metal nanoparticles present
an exceptional candidature for effectively transporting the drug molecules across the membrane
barriers while enabling the theranostic applications at the same time. The biodegradability of
polysaccharide based drug delivery systems ensure a sustained release of the encapsulated drug
molecules, which minimizes the side effects caused by a burst release of the cargo therapeutics.
These drug delivery systems proved highly beneficial for the NSAIDs that otherwise manifest
ulcerogenic effect in the gastrointestinal tract. The large surface area of polysaccharides further
provide a higher drug-loading capacity, which maintains the optimal concentration of the cargo
drug at the target sites. The emerging applications of biodegradable polysaccharides in the
designing of multicompartmental microspheres revolutionized tissue engineering, multi drug
delivery, and cell culturing technologies. The present review deals with the current-status of
polysaccharides as advanced drug delivery systems.
Introduction
Polysaccharides comprise of repeated mono- or disaccharide units connected via enzyme-
susceptible glycosidic bonds, which support their applications as controlled release drug carriers.
Their remarkable physicochemical and physiological properties such as biocompatibility,
biodegradability and low immunogenicity [1-4] further validate the drug delivery applications.
Usually, such natural polysaccharides are easily available from the plant, animals and microbes.
Such polysaccharides possess various physicochemical properties such as being neutral or having
positive or negative charge, being able to have linear or branched molecular structure, and their
molecular weight can vary from a few hundred to several thousand Daltons [5-7]. Due to these
properties, the polysaccharides have considerable impact on the biodistribution of carrier drug
molecules in-vivo [8, 9].
Numerous polysaccharides could even adhere to the layer of mucus, which covers epithelial
surfaces throughout the body. Thus, the polysaccharide based carrier systems have extended in
vivo residence time in gastrointestinal (GI) tract, thereby increasing drug bioavailability [10-14].
Cationic polysaccharides such as chitosan and its derivatives have the capacity to open the tight
interconnections among epithelial cells, thereby increased hydrophilic drug permeability through
mucus membranes [15-20].
The polysaccharides possess an inherent ability to recognize specific receptors, which over-
express on the surface of morbid tissues. As such, hyaluronic acid specifically binds to the over-
expressed CD44 receptor of several tumor cells [21]. In addition, pullulan reportedly possesses a
high specificity towards asialoglycoprotein receptors that express at the surface hepatocytes [22].
The unique binding of these polysaccharides with certain receptors permits a rational designing of
novel carriers, which selectively deliver the cargo drugs by means of receptor-mediated
endocytosis [23-26].
Besides, the polysaccharides present extensive applications as multi drug-delivery systems,
In this review, we present a comprehensive survey of the advanced applications of Polysaccharides
in drug delivery and other biomedical applications and the various factors that determine the
efficacy of these applications.
Physicochemical Factors
The alterations and chemical modifications of the functional head groups such as –COOH, -NH2,
and -OH on the polysaccharide structures led to the generation of polysaccharide derivatives with
distinct properties for specific applications. Reportedly, the sulfonation of Pullulan ameliorates its
anticoagulant activity compared to the non-sulphated counterpart. Whereas the thiolation of
chitosan significantly improves its mucoadhesive properties compared to the non-thiolated
counterpart [27, 28] owing to the formation of tight covalent bonds with cysteine-rich mucus
glycoprotein subdomains by the former [29, 30].
The interactions with functional head groups on polysaccharides enables the incorporation of
therapeutic drugs into the main chain through covalent bonds or electrostatic interactions followed
by subsequent release of the incorporated drug at target site under a suitable stimuli [31, 32].
Similarly, the amphiphilic derivatives of polysaccharides prepared by tethering the hydrophobic
moieties to the parent chain possess self-assembly properties in physiological settings and present
applications for the delivery of hydrophobic drug molecules such as paclitaxel to the target cells
[33-36].
Zeta potential also plays an important role in the drug delivery applications by polysaccharides by
influencing the interactions of polysaccharide nanosystems with proteins and cells [37]. The
factors that generate a net charge on the surface of polysaccharide nanocarrier contribute towards
the production of a high zeta potential. The dissociation of ionogenic surface group or adsorbed
molecules, and the presence of other ions in parent solvent or on the surface of the molecule offer
a significant contribution towards the zeta potential of non-ionogenic polysaccharides. However,
when the aqueous medium has no other electrolytes, the hydroxide ions adsorb on the surface of
polysaccharide resulting in an overall negative surface load [38, 39].
The pH value of the medium in addition to the ionic strength, particle size and particle density
considerably influence the zeta potential [40-42]. Acidic pH promotes the adsorption of protons
due to increasing concentration (the zeta potential increases) while a reverse effect takes place at
basic pH due to the elevated concentration of hydroxide ions. At a certain pH level, the zeta
potential may become zero, leading to instability in the colloids and accumulation of particles.
Increasing electrolyte rates in the parent medium usually result in the shielding of electrical
charges. This result in to the compression of the electrical double layer that contributes to less
electrostatic repulsion and colloid coagulation [43-45].
The phosphorylated chitosan-based micelles have been studied for their effect on mucosal drug
delivery during the change in zeta potential. On contacting the alkaline phosphatase (cell surface
glycoproteins found in many organs such as the intestine, the lungs and the vagina), the
phosphorylated micelles undergo a split off to make the zeta potential from negative to positive or
neutral [46-48]. An initial negatively charged surface enables the micelles to resist the binding of
polysaccharide to negative charged components of the mucus and diffuse through the layer of the
mucus. Whereas, a subsequent positive charge enhances the contact of polysaccharide with mucus
and cell membranes thereby preventing the back diffusion, cellular premising and internalisation
[49, 50].
Biodegradable polysaccharides or biopolymer-based nanomaterials disintegrate during their
intended function in physiological settings [51]. These polymers degrade in situ to generate the
natural by-products such as water, carbon dioxide, and small organic molecules [52]. The
backbone of these polysaccharides include functional groups of ester, amide, and ether that
undergo enzymatic degradation in physiological environment [53]. Their structure
and composition dictates the mechanisms of their degradation [54-56].
The backbone of polymeric materials consists of chemical bonds including polyesters,
polyamides, and polyanhydrides that offer numerous implementations. The polymeric materials
composed of carbohydrates consists of large chains of monosaccharide units that by hydrolysis
produce the monosaccharide portion or the oligosaccharide component. Their constructions
vary from linear to highly branched polymers. Minor differences in polysaccharide molecules can
lead to a substantial difference in the properties [57]. As such, even the minor stereochemical
differences in starch and cellulose result dramatically different functions. Click chemistry and
radical polymerization techniques bind several polymers to the cellulose backbone due to the
presence of several functional head groups on the polymeric backbone. Especially, the green
polysaccharides have been of recent interest because their biodegradability and the materials based
on these polysaccharides are ideal for absorption and subsequent removal from the body and the
systemic circulation. Interestingly, the 500 odd species of bacteria in the intestinal tract make this
environment an exceptional microbial ecosystem. The gut microbiota conduct a simple series of
biochemical processes involving starch breakdown, vitamin synthesis, and fermentation, while the
polysaccharide oxidation happens in the intestines [58]. A great deal of research has been done
focused on alkaline polysaccharide degradation based primarily on 100 ºC or less temperatures to
evaluate processes of degradation, kinetics of degradation, and interactions between structural
composition and environment [59-63].
The polysaccharides do not convert into acids at low temperatures, while in an alkaline solution,
both the starch and cellulose thermochemically degrade to water-soluble compounds [64, 65].
These properties support the colon-targeted release of the cargo drug molecules and prevent their
premature release in the acidic pH of the stomach [66].
Mainly, the alkaline degradation of starch provides products such as starch and cellulose, in
addition to small organic compounds such as acetic acid, formic acid, lactic acid, glycolic acid, 2-
hydroxyvaleric acid, and 2-hydroxybutyric acid. The second-order kinetics with the Arrhenius
equation for reactivating energy of 165 kJmol-1 explains the decay of starch and cellulose in
alkaline solution [67]. The thermal decomposition investigations of polysaccharides calculated
utilizing a slit viscometer for sodium alginate, carrageenan, and carboxymethyl cellulose (CMC)
was reported with results indicating alginate to be much less robust than CMC and carrageenan
[68-69]. The activation energy for carrageenan reportedly appeared as 104 kJmol-1, while alginate
displayed 50.7 kJmol-1 activation energy, with CMC to be 79.9 kJmol-1 [70].
BIOTOLERANCE
A major attribute to PS-based nanomaterials, in addition to their biocompatibility, is their
physiological tolerance towards the live cells. Polysaccharides reportedly exhibit strong propensity
to aggregate based on the concentration of hydroxyl or amino groups involved in hydrogen
bonding within the macromolecules. The reversible interactions primarily happen at increased
concentrations of the polysaccharide and decreases again after the sample dilution. Further, the
polyelectrolyte concentration significantly effects the multilayered structure and the density of the
polysaccharide materials. Reportedly, the polysaccharide concentrations between 0.1% and
0.5% play a significant role in the construction of multilayered structures [71-75]. The charge on
polysaccharide surface determine the aggregation of their colloidal solutions where different
surface charges are liable for multiple polysaccharide behaviors. The pH and the ionic intensity of
the media further influence ionization levels of the polysaccharides, and hence the complex
formation and phase segregation of low polyelectrolytes are generally associated
with polysaccharide-based nanomaterials [76].
Effect of pH
Within the last few decades, the pH-dependent swelling-shrinking induced behavior resulted in the
formation of new polysaccharide NPs that received significant interest in drug delivery [77, 78].
The stimuli-responsive therapeutics release rely on different interactions induced by
the aqueous property, polymeric backbone, and pharmaceutical structural composition [79-82].
Researchers, therefore, evaluated the swelling behavior of polysaccharide NPs in buffer solutions
of various pH values and reported that the swelling efficiency increased with pH value, indicating
clearly that polysaccharides NPs present a good candidature for a drug carrier with the ability to
sense variation in surrounding pH. Several polysaccharides exhibit an
outstanding tolerance towards wide pH conditions, salt concentrations, while displaying an
excellent thermal stability [83]. Depending on the gastrointestinal (GI) secretions, the rationally
designed sustained-release formulations of polysaccharides depend on pH of the environment, and
cationic charge [84-85]. As such, the carboxy groups present on the polysaccharide offered pH-
sensitivity to the dextran-based NPs. Zhang and coworkers documented unique pH- and aqueous-
force-sensitive hydrogel membranes wherein pH-dependent swelling appeared in the acidic side
chains of the polysaccharides [86-87]. More recently, by grafting synthetic poly(acrylic acid)
copolymer (D-A copolymer) on dextran, the researchers designed an altered copolymer that
displayed biotolerance, biodegradability, biocompatibility and pH-sensitivity. This
polysaccharide-based system effectively delivered Ibuprofen in the phosphate buffer solution
(PBS) at pH 2.0 and pH 7.4. The findings further indicated the pH-responsiveness of copolymer,
which enhanced with increase in the molar ratio of AA/dextran [88].
Effect of ionic strength
Another variable that affects the particle size is the ionic strength of the solvent and the
concentration gradient that plays a significant role in designing the materials with drug delivery
applications [89]. The alternative crystalline structure and amorphous cellulose structure
(contributing to stability and plasticity) offer a lower rigidity to the resulting nanofibrils at high
ionic strength [90]. At moderate ionic strength, the polysaccharides-based nanomaterials promote
stem cell replication without inducing cytotoxicity or inflammatory effects in vivo [91].
Polysaccharide based nanomaterials are often responsible for in vitro anti-inflammatory effects on
human keratinocytes [92]. One of the critical elements to evaluate the tolerance of the immune
system towards polysaccharide-based drug delivery systems is through the evaluation of dendritic
cells (DCs), which are the central inherent immune cells that regulate the immune response to
specific nanomaterials [93]. DCs can also promote immune resistance by producing ILT 3, ILT4,
indoleamine-dioxygenase (IDO)-1, and cytokine IL-10. Inflammatory and regulatory populations
of T cells may also contribute to the regulation of inflammatory diseases. The DCS are the primary
goal in diagnosis with tumors, infectious disorders, persistent inflammatory problems, implant
recognition, and wound repair [94-96]. The polysaccharide-based nanomaterials reportedly induce
adequate immune tolerance by recruiting the differential human DCs that can down-regulate Th1
and Th17 cells and up-regulate Th2 and Treg in vitro [97-99].
THERANOSTICS
The application of biodegradable polysaccharides for an effective drug delivery and bioimaging
of the drug activity in the target morbid tissues is becoming rapidly desirable. The biodegradable
natural polymers based on polysaccharides present extensive applications as tablet binders and
viscosity liquid or emulsifying agents. The polysaccharides used as coating agents ensure the
avoidance of an undesirable product flavor, enhancement in medication safety as well as
improvements in pharmaceutical volume, and release rate [100]. The short half-life of deliberated
pharmaceuticals requires multiple injections or doses, which continues to raise adverse effects and
medication expenses. In the case of poor patient adherence, multiple dosing is also problematic.
To solve these issues, the process of drug delivery to patients improved by adding biodegradable
polymers for medication encapsulation [101]. The crosslinking of the cargo pharmaceutical with
biodegradable polymer releases on a continuous or regulated basis from the encapsulating
polysaccharide. Mainly, the extent of crosslinking in the encapsulating polysaccharide material
determines the release profile of cargo drug molecules. The placement of the cargo pharmaceutical
into a hydrogel such as CMC polymer generates several pores created by hydrolysis and other
ways of degradation, which allows a controlled release of the cargo drug [102].
Polysaccharide-based contrast agent
For engineered polysaccharide-based NPs as theranostic nanomaterials, the efficacy depends on
the route of operation, retention period and the form of imaging and therapy. The selected
polysaccharides and their key characteristics, including the size, and structure poses a significant
impact on the theranostic applications. The amphiphilic polysaccharides containing stimuli-labile
linkers or hydrophobic moieties serve as a useful theranostic material [103]. Bio-
reducible disulfide connectivity cleavable in the intracellular environment prepared by chemical
modification of Carboxymethyl dextran (CMD) to lithocholic acid presented interesting
theranostic applications [104]. In another study, doxorubicin released in PBS with 10 mm of
glutathione, a tripeptide that intracellularly reduces disulfide bond in selective and robust
polynomial nanomaterials [105]. The reported nanomaterial improved the biodistribution of the
cargo drug in tumor cells as indicated in the labelling experiments. As a result, antitumor efficacy
in vivo of DOX-loaded NPs was considerably higher in comparison to reduction-insensitive NPs
of CMD [106]. Furthermore, cucurbit [6] uril-conjugated to (CB [6]-hyaluronate)
was developed as a model of the desired imaging system (Jung, Park et al. 2011). The decoration
of this complex framework with FITC-spermidine (spmd) and/or the formyl-peptide receptor-like
1 (FPRL1) resulted in the formation of (FITC-spmd and/or peptide-spmd)@CB[6]-HA
nanosystem used effectively to image its target-specific delivery in human breast adenocarcinoma
cells (FPRL1 / MCF-7) with elevated Ca2+ and phosphorus-extracellular signal-regulating kinase
(pERK) [107]. Qu et al. 2021 reported advanced delivery system based on the nanocellulose-
containing microparticles that offered ROS-trigger release of doxorubicin. The microparticles
consisted of light-sensitive shell containing Indocyanine green, which generated ROS on near
infrared laser irradiation, eventually causing the degradation of cellulose nanocrystals present in
the microparticles [108]. This bioinspired system based on ROS-mediated wood degradation by
brown-rot fungi possessed minimal toxicity and non-immunogenicity that further validated its drug
delivery applications. Further advancements led to Gas-shearing fabrication of
multicompartmental microspheres obtained from water-soluble cellulose acetate, ethyl-cellulose,
and cellulose-acetate-phthalate. The utility of biodegradable polysaccharides instead of the oils
and surfactants for the generation of monodisperse multicompartmental microspheres led to the
achievement of cytocompatibility by the microparticles. In addition, the oil-free gas-shearing
process allowed the design of microparticles up to eight compartments with a precise control over
the properties of each of these compartments. These microspheres offered applications in
biomedical engineering due to their ability to carry multiple materials in separate phases. These
microparticles presented applications as multidrug delivery vehicles, multitarget detection,
multienzyme tandem reactions, and in cell culturing technologies. The robust candidature of these
microparticles in tissue engineering resolves the key challenges associated with cellular delivery
in the current bioengineering paradigm [109]. The recent fabrication of coaxial electrospun core-
shell fibers based on cellulose acetate offer a sustained release of the biological compounds
necessary for promoting plant growth, and promote tissue healing in plants. The impregnation of
these fibers with polyurethane provides mechanical strength and enhances the modulus of
elasticity that further result in the development of plant wound dressings. Initially, the core-shell
fibers displayed 50% release of the encapsulated material in 72h, followed by a slower release that
occurred mainly due to the hydrophobic nature of cellulose acetate. This release profile however
discouraged the sustained release application of core shell fibers. The hydrophilicity of cellulose
acetate and hydrophobicity of coaxial polyurethane caused the loading of cargo drug in the latter
due to the poor affinity of the drug with water. Notably, the encapsulated drug displayed two-stage
release kinetics from the cellulose acetate-polyurethane coaxial electrospun fibers [110].
Superparamagnetic iron oxide nanoparticles possess characteristic magnetic properties for
bioimaging applications. Their coating with polysaccharides provide robust drug delivery
materials with theranostic applications [111, 112]. Furthermore, as an innovative method for
achieving a controlled drug delivery and bioimaging applications, superparamagnetic iron oxide
nanoparticles coated with hyaluronan (HA) (HA-FeO). The target cancer cells rapidly uptake HA-
FeO nanosystem on incubation for 24h [113], and HA-FeO internalization into the cancerous cells
was far higher than NPs without HA fabrication. Notably, the high magnetic relaxation and
increased utilization of HA-FeO promote cancerous cell imaging. The anchoring of DOX via an
acid-responsive linker to the NPs further promoted a controlled release of the drug. DOX-HA-FeO
system was far more potent than free DOX in offering therapeutic properties against the multidrug-
resistant cancer cells [114]. Choi et al. 2010, identified the simultaneous delivery platform for the
gene/drug, and tumor by using chitosan functionalized magnetic graphene (CMG). The
nanosystem provided a robust candidature as T2 contrast-improving agent as indicated by the
phantom tube experiments and ex vivo MRI. As measured by the WST method, CMGs
concentrated mostly on the tumor cells, as demonstrated by distribution studies and MRI [115].
Heparin-folic-IR-780 (HF-IR-780) multifunctional NPs synthesized by self-assembly through an
ultrasonic sound method specifically targeted the tumor cells while providing the bioimaging
applications. Assays on in vitro cell viability and photothermal in vivo therapy show a mixture of
HF-IR-780 NPs with 808 nm laser radiation in the shape of MCF-7 or xenograft MCF-6 cell tumors
[116]. Glycolated chitosan based Bcl-2 siRNA complex provided applications in gene therapy in
addition to providing theranostic applications for the imaging of solid tumors. Further, the
polysaccharide-based nanomaterial assisted the targeted delivery of doxorubicin to the target
cancer cells [117].
Polysaccharide-based drug delivery systems
The differential pH gradient between the tumor and healthy tissues, as well as between cytoplasm
and endosome serves as essential stimuli for smart drug delivery applications. The four specific
approaches utilized to design the pharmaceutical carriers include drug conjugated to the
polysaccharide, entrapment of therapeutics through in aerogels and hydrogels, formulation of
drug-loaded polysaccharide nanoparticles (NPs) through the self-assembly. Figure 1 highlights the
various types of interactions between the drug molecule and polysaccharides.
 Figure 1. The types of interactions between the polysaccharides and drug molecules
MODIFICATION OF POLYSACCHARIDES
Physical Interactions
Polysaccharide molecule containing functional head groups on their surface undergoe chemical
modification for conjugating with the desired drug molecules [118]. Specifically, the -OH group
present on the polysaccharide undergoes esterification or etherification with acylating and
alkylating agents respectively [119-120]. This group undergoes further oxidation to –COOH and
–CHO groups in the presence of a suitable oxidizing agent that further extends the chances of
conjugation with a diverse range of functional groups on the cargo molecule. The –COOH group
and –NH2 functionalities in polysaccharides undergo amidation, hydrazone formation, and Schiff
base modification to conjugate with the cargo drug molecules [121-123]. Typically, the formation
of polysaccharide gel requires a chemical or physical cross-linking of the polysaccharide for
encapsulating the therapeutic molecules [124-127]. Mainly, the physical cross-linking of
polysaccharides involves simpler preparation protocols devoid of chemical reagents [128]. The
polysaccharides containing –COOH or –NH2 groups reportedly undergo ion complexation to
generate the physically cross-linked nanohydrogels with myriad applications as drug delivery
vehicles [129]. Typically, the anionic polysaccharides generate hydrogels by interacting with metal
cations, while the cationic polyglucosamines interact with multivalent metal anions [130-131].
Similarly, the negatively charged alginic acid displays cross-linking interactions with CaCl2,
whereas the positively charged chitosan readily interacts with sodium tri-polyphosphate [132-
134]. Notably, the carrageenan polysaccharides contain sulfonate group along their backbone that
serve as a site for cross-linking with metal ions as well as cationic polymers such as chitosan [135-
137].
The interactions between the dissimilarly charged polymers result in the formation of
polyelectrolyte complex [138]. Mainly, the ionic interactions in the polyelectrolytes exhibit a
superior strength compared to the van der Waals forces and hydrogen bonding interactions [139].
The negatively charged polysaccharides including hyaluronic acid, pectin, xanthan,
carboxymethyl cellulose, alginic acid, and chondroitin sulfate form the polyelectrolytes [140-142].
(Boddohi et al. 2009; Wu et al. 2020; Potas et al. 2020). In addition, the proteins such as albumin,
gelatin, collagen, keratin, and synthetic polyacrylic acids reportedly generate polyelectrolytes
[143].
Hydrophobic interactions result in the physical cross-linking of polysaccharides for maintaining
the structure and morphology. The anchoring of hydrophobic groups to the polysaccharide chain
lower the water solubility and promote hydrophobic drug delivery [144]. The amphiphilic
copolymers prepared by entrenching the hydrophilic polymeric backbone with hydrophobic
structures, orient themselves to achieve a minimum free energy state, while the hydrophobic
portion disengage from the aqueous environment thereby forming core shell structure of polymeric
micelles [145]. The structures containing hydrophilic outer shell enclosing the hydrophobic
interior serve as carrier for hydrophobic drug molecules [146]. The modification of
polysaccharides with long chain fatty acids such as palmitic acid, stearic acid, linoleic acid,
linolenic acid, and hexanoic acid result in the generation of polymeric micelles [147-148].
Similarly, the conjugation of polysaccharides to hydrophobic polymers such as poly
(ɛcaprolactone), poly (isobutyl cyanoacrylate), poly (ethylene glycol) derivatives, and pluronic
copolymers generated the desired core-shell drug delivery systems with hydrophobic core and
hydrophilic shell [149]. Nevertheless, the presence of polar groups such as –OH, -COOH, -NH2 in
polysaccharides participate in hydrogen bonding interactions that play a critical role in drug
delivery applications. The polysaccharides such as chitosan forms hydrogen bonds at pH > 5,
whereas it requires low temperature and pH to form hydrogen bonding in agarose [150]. Similarly,
the synthetic polysaccharide carboxymethyl cellulose demonstrates pH sensitive hydrogen
bonding interactions, which form the basis of drug delivery applications in these polymeric
systems [151].
Chemical modifications
The chemical modification of polysaccharides led to their conjugation with drug molecules via
functional head groups through the covalent bonds. These chemical modifications followed by a
subsequent conjugation mainly occur via nucleophilic replacement of the saccharide oxygen by
heteroatomic nucleophiles. Typically, a saccharide electrophile possesses lower reactivity towards
the nucleophilic substitution compared to the other hydrocarbon-derived molecules [152]. The
destabilization of carbocation generated at the primary or secondary position due to the presence
of surrounding electron withdrawing –OH groups increases the difficulty of SN1 reaction at the
primary and secondary positions, as compared to the SN2 reactions at the same position [153].
The bulkiness of the alkoxy and acyloxy substituents further lower the reactivity of saccharide-
derived electrophiles toward SN2 reactions [154]. Especially, the higher stability of the chair
conformation of the six-membered saccharide ring and the presence of multiple equatorial
substituents makes it difficult for the completion of an SN2 attack the secondary position of the
target saccharide [155]. Mechanistically, the formation of SN2 transition state involves changes in
the ring conformation for accommodating the attacking nucleophile, and the leaving group around
the central carbon. However, the highly stabilized chair conformation refuses to undergo these
conformational changes as it results in less favored strained conformation [156].
The replacement of primary and secondary –OH groups in saccharide molecules with a good
leaving group improves the susceptibility of electrophilic carbon towards the nucleophilic attack.
Mainly, the halide ions, and the less reactive functional groups such as phosphonate and sulfonate
prove better leaving groups at the primary position. While the groups such as triflates and epoxides
serve as better leaving groups at the secondary position. The nucleophilic reaction by a saccharide
nucleophile through the ‘O’ atom result in the acylation or alkylation of the polysaccharide,
whereas the nucleophilic attack on polysaccharide molecules by alcohols or carboxylates for the
formation of ether and esters occur less commonly [157]. The esterification of polysaccharides
occurs preferably via Mitsunobu reaction, which incorporates an in situ activation of the -OH
group by phosphonium leaving group, where the attacking nucleophile facilitates its departure
[158]. The high-yielding, regioselective Mitsunobu reactions mainly occur at the primary position
of unprotected saccharide units [159]. Amine group acts as neutral nucleophile for modifying the
polysaccharide with alkyl chains. Preferably, the monovalent properties of the azide nucleophiles
prevent the multiple side reactions or cross linking of the parent polysaccharide. The azide
functionalization of polysaccharides proves highly beneficial for their click conjugation to the drug
molecules or biomolecules bearing a propargyl substituent [160]. The click conjugation of
polysaccharides with desirable drug molecules via strong triazole spacer improves the in vivo
stability and the pharmacokinetics of the drug delivery system [161-162]. Particularly, the click
conjugation presents extensive applications in molecular medicine where the cargo therapeutics
bind with desired biomolecules including polysaccharides, antigens, nucleic acid sequence,
mRNA, and peptides [163]. Likewise, the thiols participate in nucleophilic substitution with
polysaccharide rings that contain halides as leaving group.
 NH(CH 2)7CH 3 OH OH OH
O
O O O
O PPh3 / CBr 4
O O
O OR NaN 3 / DMF
H 3C(H 2C) 7HN O OH OH
OH OH
O O N3
O Amidation Ugi reaction
NH O
NC
OH OH EDC/ CMPI O
CH 3(CH 2)7NH 2
OH OH
Esterification HCHO/ CH 3(CH 2)7NH 2
Azide formation
(ROH/ catalyst) OH OH
OH O O OH OH
O HO
O O O
O HO O OH O
O
OH OH
OH O
O Polysaccharide O
O OH O
OH OH
Reductive
Amination
Oxidation Sulfation
(NaIO4) O OH (ClSO3H/ formamide)
O
O OH
O OH
O
O HH
O O O O
HH
NH 2R O
O O
O OH NaCNBH 3 O OH OH OSO3H

O O
O O
HH
N N HN NH
R R R R

Figure 2. Chemical modifications on polysaccharides

Figure 2. Illustrates the various chemical modifications done on polysaccharides at the free –OH,
and –COOH groups. The oxidation of polysaccharides at the –OH groups on C2/ C3 position to
yield aldehyde groups causes a faster degradation in physiological background when used as
controlled drug delivery carriers. The conversion of hydroxyl substituent to aldehyde groups
provide a rotational freedom to the parent saccharide units, however it requires precautions such
as light exclusion to prevent the occurrence of any side-reactions, in addition to limiting the
concentration of the oxidant in order to achieve a controlled oxidation of alginate [164]. Notably,
the oxidized polysaccharide completely degrades at the physiological pH = 7.4 at 37 oC, thereby
making it an excellent drug delivery carrier [165]. The oxidation of polysaccharide units results in
the formation of reactive aldehyde groups, thereby encouraging further chemical modification by
reductive amination. The conversion takes place in the presence of suitable reducing agents that
selectively reduce the imine intermediate, over the starting aldehyde group [166]. The reductive
amination of polysaccharides with long chain alkyl amines provides amphiphilic properties to the
parent polysaccharide, and lower their surface tension for a better physiological absorption. This
drug delivery system ensures a better loading capacity of hydrophobic drug molecules for
achieving a controlled drug release profile. The structural similarity of sulfated polysaccharide
with anticoagulant heparin improves the blood compatibility of the test polysaccharide deliberated
for drug delivery applications [167]. The in vitro assay for appraising the coagulation of human
plasma in the presence of sulfated alginates suggested notable anticoagulant properties of the
polysaccharide by targeting the intrinsic coagulation pathways [168]. Similarly, the esterification
of polysaccharide acids with alkyl groups improves the hydrophobicity of the parent
polysaccharide. Furthermore, the synthesis of alginate bis-amides via Ugi reaction presents an
important modification of polysaccharides for their drug delivery applications.
Polysaccharide-drug conjugates
Numerous natural and synthetic water-soluble polymers reportedly exhibit conjugation with
therapeutic molecule through chemical conjugation [169]. Pharmacokinetic investigations of
drug-conjugating polysaccharides have documented the implications of natural and sustainable
polymers as robust drug delivery systems. In addition to the synthetic, water-soluble polymers, the
natural polymers such as dextran, chitosan, hyaluronic acid, and cellulose seem to have a
tremendous drug carrier potential [170]. Coupling of the hydrophobic doxorubicin (DOX) with the
acid-cleavable hydrazone bond generated DOX-chitosan nanoconjugates with pH-sensitive drug
release [171]. The study revealed that the chitosan-DOX conjugates with the acid-cleavable
hydrazone bond became stable at neutral pH and dissolved at pH 5.0, which made a significant
contribution to the eruption of DOX into HeLa cells. Prodrug NPs internalized rapidly to illustrate
its potential applications in tumor-targeted pharmaceutical materials, contributing to a substantial
accumulation and deposition of DOX in HeLa cells [172]. Simple carbohydrates, such as dextran
reportedly utilize in the recombination of medications. Bacterial strains, including Leuconostoc
and Streptococcus produce copious amounts of dextran polysaccharide, including the primary and
secondary categories of dextran that offers possible therapeutic conjugation regions with specific
methods [173-174]. Reportedly, the destroying the impact of free curcumin on cancerous cells
diminishes with time, whereas the cytostatic activity effects of curcumin-loaded chitosan NPs of
the same concentration range on MCF7 cells improved significantly in the incubation period.
Furthermore, the chemical tailoring of such materials offered selective and more efficient drug
delivery to tumors due to the predominant amine and hydroxyl groups on the chitosan framework
[175]. For the delivery of paclitaxel (PTX) and docetaxel (DTX), Skorik et al. used chitosan-based
NP as nanocarriers. The drug-charged succinyl and glutaryl chitosan NPs displayed a considerable
cytotoxicity towards the gastrointestinal cell lines and thus increased their anticancer activity
compared to free drugs. Due mainly to a tumor-homing ligand (3-carboxyphenylboronic acid), the
updated carboxymethyl chitosan-based NPs loaded with DOX demonstrated an increased
accumulation concentrations and penetration into tumor presenting mice with H22 lung
metastasis. This significantly reduced the mass of the H22 metastases lung tumor by further
infiltration and aggregation of NPs in the tumor site.
D-glucuronic acid repeats and D-N-acetilglucosamin disaccharide conjugate to generate
the hyaluronan (HA) by means of β-1,4- and β-1,3-glycosidic links [176]. The hyaluronate
framework comprises of hydroxy and carboxyl groups, which participate for the conjugation with
several drug molecules. Considering the steric hindrance and weak carboxyl reactivity, direct
conjugation could is not preferred [177-178]. HA derived products that have the functional head
groups such as hydrazine (-NH2-NH2-) improve the reactivity and drug conjugation efficacy. HA
derivatives that require carboxylic acids to be substituted and functionalized also display increased
drug loading with limited alteration in the polysaccharide structure [179]. Paclitaxel (PTX) was
elevated in loading and reduced product toxicity relative to free PTX in conjugations with HA-
deoxycholic acid coupled to bio-reducible cysteamine. The binding effects of the medication
retains even after a significant degree of replacement. Several methods reportedly cope with the
low solubility of HA in conventional organic solvents, which hampers cytotoxic conjugation
reactions [180]. Those methods include the use of combinations of polar solvents with water,
polyethylene dimethyl ether nanocomplexation and ion compositions of long-chain aliphatic
cations [181]. The application of HA-drug conjugates offer a selective targeting of the excessive
CD44 overexpressed receptors [182]. HA-conjugated products, including HA-mitomycin C, HA-
epirubicin, HA-butyrates, and HA-paclitaxel present robust applications in drug delivery. Notably,
the inhibitor of histone deacetylase demonstrated enhanced apoptosis activity, resulting in reduced
in vivo tumor load and inhibition of in vitro cell development on its conjugation with HA [183].
The usage of N, N'-dicyclohexylcarbodiimide (DCC), and cholic acid derivatives (Colic acid) have
modified sucrose and poly(d, l-lactic-co- glycolic acid) (PLSGA) through crosslink. This
represents an exciting development for a controlled system of drug delivery for medications with
low aqueous solubility [184]. Numerous uses featuring various composite hydrogels composed of
polysaccharides including chitin, nanocellulose and chitosan offered advanced pharmaceutical
delivery systems, enhanced regenerative medicine, tissue engineering, wound dressings, and water
purification sorbents [185]. Chitin composites can be generated in spherical nanogels, in
conjunction with rhodamine 123 dye that improved the drug distribution provides applications in
tissue engineering [186, 187]. The polysaccharides conjugated to folate, fluorescent functionalities
maintain an optimal drug loading and drug release profile and present potential applications for
gene therapy on specific positions, including cancerous cells [188]. Development of wound
treating products based on Pectin in the recent years combined with cellulose and micro fibrillated
cellulose offered promising results in vivo. The findings on animal models were encouraging, but
further experimental tests were required for clinically success. Pectin presents applications in
medicinal sprays as a drug carrier for the administration of drugs. The Pectin incorporated nasal
spray drug such as fentanyl that relieves pain in cancer and contributes to better chemotherapy
treatment [189]. Figure 3 depicts the main strategies for drug encapsulation by polysaccharides.
 Figure 3. Drug loading strategies by Polysaccharide nanoparticles
Drug retention in aerogel layer and hydrogels
Hydrogels represent 3-D hydrophilic, polymeric platforms, which hold potential preserve large
quantities of water or biological fluids. Aerogels are extremely porous and provide large internal
surfaces with exceptional drug delivery capabilities [190, 191]. Almost all of these gels are static
and brittle; however, polysaccharides form xerogels and they tend to generate transparent
hydrogels, which spontaneously shape interconnected polymers. The morphological and chemical
features of a gel rely on the consistency of the formulated aerogel. For the processing and
distribution of chemically stable hydrogels and aerogels, the utilization of hydrophilic
polysaccharides and their precursors offer selective delivery of therapeutics [192, 193]. The
association of a polyelectrolyte with an opposing multivalent ion by dynamic co-conservation
determines the properties of ionotropic hydrogels. Hydrogels are sensitive to different
environmental conditions including pH, ionic strength, and temperature that influence their
characteristics and morphology [194, 195]. In certain settings, it is feasible to provide a long-
lasting release for up to three months of nanofibrillar cellulose for long-term pharmaceutical
applications [196]. In an attempt to improve the structural strength and the swelling-deswelling
abilities of the polymer, engineered single networks to the hydrogel reduced the structural strength
to obtain the interpenetrating polymer (IPNs). The IPNs constitute of the interconnecting polymer
network formed by linking two different polysaccharides. In this context, gelatin-grafts-
polyaniline and carboxymethyl chitosan were prepared as injectable coordinating IPN hydrogels
with enhanced mechanical proprieties, crosslinked in physiological terms with oxidized dextran
via the Schiff base formation. The evaluation of hydrogels for in vivo biocompatibility
demonstrated a tremendous potential for drug and tissue development [197]. Alginate is a charged
biopolymer consisting of repetitive disaccharide units comprising of 1-4-linking β-D-mannuronic
acid and α-L-glucuronic acid organized in separate blocks or alternating blocks at different
proportions. Researchers have been able to establish advanced techniques for the distribution of
natural pharmaceutical medications with the use of ionic and covalent combinations to form
Alginate-based gels [198]. The redox-sensitive alginate offers applications in the construction of
hydrogels and nanogels using carbodiimide interconnection. Gels developed using redox-
degradable polymers dissolve to release the cargo medicinal product. The poly(diallyl
dimethylammonium chloride) (PDADMAC) conjugated with alginate provides temperature- and
pH-sensitive hydrogels in drug delivery applications. The pH behavior of the hydrogels implies
total swelling at pH 4, due to the ionization of the COOH groups in alginate, induced by
electrostatic repulsion [199]. In comparison, polyelectrolyte complexes, PDADMAC coexist with
ionized COOH, resulting in a diminishing swelling ratio [200]. Alongside the swelling attribute,
investigators often build a framework for the controlled released of therapeutics with other
features, including superporosity and electromechanical sensitivity. Several attempts aimed at the
colon-targeted delivery of rabeprazole sodium by the implementation of biodegradable polymers
for its mucoadhesive properties, generated from crosslinking O-carboxymethyl-chitosan and
carbopol with a Ca2+ ionic cross-linking [201]. CMSP hydrogel displays the
ionic crosslinking with Al3+ for colon-targeted drug delivery. A CMSP hydrogel, filled with 5-
aminosalicylic acid (5-ASA), released small levels of 5-ASA at stomach pH and maintained the
release of drugs at colonic pH. The manufacturing of the polymer from industrial waste further
promised minimization of pollutants as well as the costs of formulation [202]. Glutaraldehyde
effectively controlled the release of Buflomedil hydrochloride through the Locust gum with
poly(vinyl alcohol). This combination appropriately controlled the rate of release to short half-
lives and improved the water solubility of the encapsulated pharmaceutical items [203]. The
psyllium-based polymers are other modified polysaccharides widely used in drug delivery
applications. The maximum effectiveness appeared at the pH 7.4 for the product buffer for
psyllium-poly(vinyl alcohol) filled with rabeprazole sodium. The hydrogels possess
hemocompatibility, which suggests their application in pharmaceutical goods for the treatment of
bloating ulcers [204].
Polysaccharide drug-loaded through self-assembling
Hydrophilic polysaccharide backbones construct the self-assembling frameworks, such as
niosomes and liposomes, when they are introduced to hydrophilic polymers [205-207]. The self-
assembly of hydrophobic polysaccharide formulates from the polymer backbones treated with
hydrophobic sections of hydrophilic polysaccharides containing hydroxy, amino or carboxy
groups that eventually form amphiphilic macromolecules. This solubilizes the hydrophobic drugs
molecules in the self-assembling drug delivery polysaccharides. The factors such as fluctuations
in pH, ionic intensity, and temperature further determine the drug release from these
polysaccharides [208]. Self-assembled nanoparticles in hydrophilic polysaccharide frameworks
such as amylose, guar gums, pectin, chitosan, dextran and rubber beans offer wider applications
in the delivery of hydrophobic drugs at the target site. The polysaccharides offer an ideal platform
for colon-target distribution since it shows high stability in the stomach pH, as compared to the
intestine physiological environment as the colon microbiota induces polysaccharide degradation
and eventually release the therapeutics payload into the colon [209]. Polysaccharide-based NPs
such as chitosan armed with therapies like paclitaxel, ibuprofen, and amphiphilic doxorubicin
(DOX) improve the overall therapeutic effect of the drug. Amino groups on Chitosan participate
in the grafting of hydrophobic groups through acylation with acyl chloride or anhydride acid and
ultimately interconnected with deoxycholic acid. Advanced applications such as plasmid DNA
transfection with deoxycholic groups-acid NPs (160 nm) was reported in COS-1 cells [210].
Dextran, often considered the self-assembled nanosized drug carrier, offers the grafting of several
biomolecular moieties such as bile acids, normal amphiphilic steroids, and lauryl strands. Azido-
modified dextran NPs mixed with mannose showed an improved cellular internalization for the
delivery of therapeutic agents. Addition of acrylic acid to dextran generated pH-sensitive NPs
between 40 and 140 nm diameter [211]. The modified dextran effectively improves the absorption
of DOX, hence proving to be a viable transporter for DOX. Dextrin nanogel filled with DOX
minimizes the toxicity of the drug towards normal human cells by reducing the therapeutics side
effects. Chemical transformation of HA to form NPs in the size range 200-400 nm, comparable to
dextran and chitosan conjugated with 5-β cholinic acid offered highly effective treatment of
inactive CD44 tumors. HA shapes amphiphilic chain copolymers when covalently linked to the
poly(γ-benzyl l-glutamate) component [212]. Not only were these nanoparticulates elevated the
cellular uptake by endocytosis, but they have also increased drug toxicity in the target KB cells
[213]. The usage of starch or cellulose-based drug delivery nanoparticles also improved their
solubility in the organic solvents by the introduction of chemical modifications on the hydroxy
and carboxyl groups. These approaches further improved the drug loading capacity onto these
nanocarriers by conjugating with the functional head groups on the polysaccharide surface [214].
 Table 1. Polyaccharides in drug delivery applications.

PS-based Therapeutic agents & Type of Cell types Model of study Polymer Advantages References
polymer targeting
Dextran COX-2 siRNA/ Passive Breast cancer cell In vitro and in vivo Biocompatible, pH stimuli- [215]
lines (MDA- responsive, down-regulate
MB231) Cyclooxygenase COX-2 genes in
tumor cells
Dextran- folic DOX/Active Breast cancer cell In vitro and in vivo Reducing the side effect of DOX, [216]
acid line (4T1) enhanced tumor growth
inhibition, and prolonged survival
rate
Dextran- Paclitaxel/ Passive Breast cancer cell In vitro and in vivo Enhanced cellular uptake, [216]
Indomethacin line (MCF-7) prolonged pharmacokinetics
(prolonged circulation time and
slower elimination), enhanced
tumor growth inhibition
Dextran- Paclitaxel/ Passive Colorectal cell line In vitro and in vivo Cellular proliferation enhanced [217]
albumin (CT-26) inhibition, inducing apoptosis,
Enhanced drug circulation times
Dextran-folic Resveratrol/ Active Lung cell line In vivo Enhanced cellular apoptosis and [218]
acid (A549) drug intake
Dextran-DOX Doxorubicin/ Passive Lymphoma cell In vitro and in vivo Reduced cytotoxicity (cardiac), [219]
lines enhanced apoptosis, enhanced
intracellular intake leading to
increased DOX concentration that
inhibits tumor growth
Hyaluronic 5-Fluorouracil/ Active Lung cell line In vitro Enhanced cell apoptosis and [220]
acid- Chitosan (A549) & cellular drug accumulation
liver cell line
(HepG2)
Hyaluronic Paclitaxel & curcumin /Active Breast cancer cell In vitro and in vivo Prolonged pharmacokinetics, [221]
acid- Poly- line (MCF-7) Enhanced cellular accumulation
lactic-co-
glycolic acid;
Hyaluronic Paclitaxel/Active Breast cancer cell In vitro Decreased the IC50 of paclitaxel [73]
acid- Poly- line significantly
lactic-co- (MDA-MB-231)
glycolic acid;
Hyaluronic Naringenin/Active Lung cancer cell In vitro and in vivo Enhanced cell apoptosis, [222]
acid- Poly-ε- line (A549) increased drug intake resulting in
caprolactone- inhibiting cancer growth
Chitosan
 Hyaluronic Paclitaxel/Active Breast cancer cell In vitro and in vivo Enhanced cancer growth [223]
acid-Silica line (MCF-7) suppression, increased intake and
drug accumulation
Hyaluronic Doxorubicin & Gemcitabine Breast cancer cell In vitro and in vivo Dual modality drug delivery [224]
acid /Active lines system, enhanced inhibition to
(MDA-MB-231 cancer growth
& 4T1)
Hyaluronic Doxorubicin & Cisplatin /Active Breast cancer cell In vitro and in vivo Tumor growth inhibitor at low [225]
acid- lines drug concentrations
Polyamidoamin (MDA-MB231
e & MCF-7)
Hyaluronic TWIST- siRNAs (Basic helix- Ovarian cancer cell In vitro and in vivo Reduced cancer growth and cell [226]
acid-Silica- loop-helix transcription factors)/ line survival through selective
polyethyleneim Active (Ovcar-8) targeting
ine
Hyaluronic 5-Fluorouracil /Active Colon cancer cell In vitro and in vivo Tumor repression, high [227]
acid-Silica line (HT29) cytotoxicity and high
accumulation in the tumor
through selective targeting
Chitosan- N- DOX/Passive Breast cancer cell In vitro Enhanced cytotoxicity and [228]
acetyl histidine lines MCF-7 cellular uptake
and arginine
 Chitosan- DOX & IL-2/Active Lung cancer cell In vitro and in vivo Increase IgG expression levels, [229]
Trimethyl and line (A549), Increased cytotoxic T
folate Liver cell line lymphocytes
(SMMC-7721)
and hepatoma cell
line
(H22)
Chitosan Suramin and Breast cancer cell In vitro and in vivo Inhibit Breast and lung metastasis [230]
DOX/ Passive line
(MDA-MB231)
Chitosan- DOX and IL17RB Breast cancer cell In vitro Decrease tumor cellular viability, [231]
Carboxymethyl siRNA/ Passive line inhibits growth, tumor cells
dextran (MDA-MB361) migration, and proliferation
Chitosan- Curcumin/Passive Colon cancer cell In vitro Enhanced cellular uptake, [232]
Hyaluronic line (HT29) reduced cellular proliferation, and
acid- high toxicity
sulfobutyl-
ether-β-
cyclodextrin
Alginate DOX/Passive Melanoma cell line In vitro and in vivo Inhibit tumor growth, higher [233]
(B16) cellular uptake, high cytotoxicity
Alginate Gold NPs (AuNPs) & cisplatin/ Colon cancer cell In vitro and in vivo Tumor growth high inhibition, [234]
Passive line (CT26) enhanced survival
Alginate Paclitaxel/Passive Different breast In vitro and in vivo Promote cell cycle arrest, induce [235]
cancer cell lines apoptosis and reduce the
bioavailability
Alginate- DOX/Active Breast cancer cell In vitro Inhibit tumor progression and [236]
chitosan line (MCF-7) cellular growth
Pullulan Floate & Cervical (Hela) In vitro and in vivo Tumor growth inhibition [237]
Polyethylenimine/Active and liver
(HepG2)
Pullulan- Paclitaxel/Active Liver cancer cell In vitro and in vivo Lower cytotoxicity due to [238]
Folate line selective targeting and prolonged
(SMMC-7721) release
Therefore, the polysaccharide offer a fascinating choice as polymeric material in drug delivery
due to biodegradability and biocompatibility. The application of polysaccharide in drug
delivery is growing very fast as it provides a safe, nontoxic and tunable alternates of synthetic
polymers for the same purpose. The diverse chemical structures, functional groups and
physicochemical properties are making polysaccharides a suitable candidate in drug delivery
[239, 240].
Polysaccharide based controlled release and targeted formulations
Unlike the synthetic hydrophilic polymers, polysaccharide possess a variety of hydrophilic
functional groups on its structure like –OH, -COOH, and –NH2 group which are responsible
for water absorption and further swelling of polysaccharide. These groups grant a variety of
functional capability to the polysaccharide-based systems such as bioadhesion and control
release property. Controlled release property of polysaccharide-based drug delivery systems
has been explored extensively for achieving a prolonged delivery of variety of therapeutics
such as chemotherapeutics, proteins, peptides, nucleic acid and many more [1]. The control
release of therapeutics from the swelled polysaccharide depends on the porosity or degree of
swelling, further regulated by certain parameters like pH, temperature, ionic strength and
electric fields [241]. Several polysaccharides present controlled release and target specific
delivery applications.
1. Chitosan: It is a linear polysaccharide obtained from the exoskeleton of arthropods such as
crabs, lobster, and shrimp and cell walls of fungi. It is available in variety of molecular weight
and degree of acetylation, which control its physical and biological property. Hydroxy and
amino groups on the chitosan are involved in making intra- and intermolecular hydrogen bonds.
The pH dependent protonation of amino group leads to swelling of the Chitosan to form three-
dimension structure gel at pH lower than the pKa [242]. Various chitosan salts such as chitosan
palmitate and chitosan laurate exhibit different degrees of swelling, and thus drug release from
the variety of dosage form. The presence of primary amines in chitosan is responsible for its
biological activity such as antimicrobial, anticancer. Chitosan nanoparticles showed greater
antimicrobial activity against Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas
aeruginosa, and Escherichia coli compared to parent chitosan and chitin [243]. Chitosan-based
controlled release and targeted formulations developed so far are compiled in Table 2.
2. Alginate: It is an extensively studied linear polysaccharide derived from brown seaweed
(Macrocystis pyrifera, Laminaria hyperborean) and from some certain bacteria belonging to
the family Pseudomonas and Azotobacter. Similar to chitosan, aginate also form a thick gel at
low pH, which served as a barrier for controlled release of therapeutics. Additionally, alginate
also form thick gel with certain polyvalent cations (Ca2+ and Na+) due to crosslinking of
carboxylic groups of polysaccharide structure. Due to the bioadhesion property of alginate, it
offers targeted drug delivery applications. So far, this polysaccharide has been explored for
variety of formulations including matrix tablet [244], microspheres [245], pellets [246] and
nanoparticles for targeted and functionalized delivery [247] (Table 2). The combination of S-
nitroso-mercaptosuccinate (a nitric oxide donor) and green tea synthesized silver nanoparticles
incorporated into alginate hydrogel showed synergistic antimicrobial activity against
Staphylococcus aureus, Escherichia coli and Streptococcus mutants compared to individual
compounds [248].
3. Pectin: Pectin is a complex polysaccharide present almost one third of the dry cell wall
material of most of the plants. These are higher molecular weight (50,000 and 150, 000 Da)
polysaccharides consist α-(1-4) linked esterified D-galacturonic moiety. Various
physicochemical parameters of pectin like solubility, viscosity and gelling properties depends
upon the degree of methyl esterification of D-galacturonic moiety. Depending upon the degree
of esterification two types of pectin are commercially available; highmethoxyl pectins (degree
of esterification > 50) and low methoxyl pectins (degree of esterification < 50) [249]. Various
plant pectins reportedly exhibit applications as controlled release excipients in tablet, hydrogels
and pellets. Additionally, plant pectins offer applications in colon targeted drug delivery due
to their biodegradation potential by colonic microflora [250]. The pectin polysaccharide from
Ulmus pumila L. (PPU) possess potent anti-inflammatory activity. It was observed that the
selenized-PPU inhibit lipopolysaccharide (LPS)-stimulated nitric oxide release by targeting the
protein expression of inducible nitric oxide synthase in murine macrophage cell line RAW
264.7 [251].
4. Guar Gum: It is a high molecular weight linear polysaccharide obtained from the seeds of
the plant Cyamopsis tetragonoloba. The polysaccharide consist of linear chain of (1 → 4)-
linked β-D-mannopyranosyl units with (1 → 6)-linked α-D-galactopyranosyl residues as side
chains with the ratio of mannose to galactose units as 2:1. This polysaccharide swells in polar
solvent and thus has been widely explored for various pharmaceutical applications. Addition
of ionic and non-ionic additives (sodium chloride and glycerin) could change the swelling and
erosion property of polysaccharide for offering a variety of applications [14]. This
polysaccharide serves as tablet binder sustain release polymer and viscosity enhancers. This
polysaccharide has become the primary choice as excipient in colon specific oral product as it
remain indigestible in upper GIT and completely degrades by the colonic microflora [252].
Gamal-Eldeen prepared guar gum C-glycosylated derivative (GG) and its sulphated derivative
(SGG) to investigate its anti-cancer and anti-inflammatory potency. It was observed that GG
inhibits cytochrome P450 1A (a carcinogen activator enzyme) and stimulated the carcinogen-
neutralizing enzymes such as glutathione-S-transferases. Furthermore, both GG and SGG were
able to exert anti-inflammatory by reducing the release of nitric oxide and tumour necrosis
factor-alpha in LPS induced RAW264.7. GG and SGG also inhibited the proliferation of human
hepatocellular carcinoma cells (Hep G2), while only SGG was particularly toxic for MCF-7
[253]. Table 2 presents the selected applications of guar gum as pharmaceutical excipients.
5. Starch: Starch is a naturally available polysaccharide obtained from plants. Its characteristic
properties such as biotolerance and non-immunogenicity for human use, and easy availability
make it a commonly used polymers/pharmaceutical excipient [254, 255]. In comparison to
other polymers such as gum and cellulose, starch does not need to undergo excessive
purification, as they are relatively pure. Structurally, starch has two different glucan chains a.
amylose (linear polymer) and b. amylopectin (branched polymer) representing 98-99% of the
dry weight. In the production of capsules and tablets, starch is widely utilized as a lubricant,
diluent, binder and disintegrant whereas it is also commonly employed for variety of
specialized drug delivery applications, for example delivery of specialized drug and targeting
specific parts of human body [256]. The microsphere of oregano essential oil prepared by
starch-based material utilizing supercritical fluid technology showed superior antioxidant
capacity (in terms of oxygen radical absorbing capacity) and stability. Starch-based drug carrier
systems present high efficacy in the oral delivery of insoluble drugs [257]. Luo et al. (2020)
encapsulated curcumin into starch microparticles and the formulation showed enhanced
stability against photodegradation and oxidative modification. Furthermore, the size of
curcumin starch microparticles was possible to control accurately from 0.3-2µm by altering the
rate of debranching reaction that caused alteration of release characteristic of curcumin. These
observations suggested the management of the release site by modifying the crystallinity or
size of microparticles [258]. Alp et al. 2019, formulated starch nanoparticles for the delivery
of epigenetic drugs CG-1521 for breast cancer that inhibits histone deacetylase. The
nanoparticles formulation showed decrease release rate of CG-1521 allowing remarkable
cytotoxicity against MCF-7 breast cancer cell as compared to free CG-1521 [259].
Table 2: Different polysaccharides explored for the sustained release of pharmaceuticals

Polysaccharide Formulation Drug Remark Ref.

Chitosan Oral Tablet Sodium valproate Extended release behavior of embedded drug upto 24 h [260]

Hydrogel Caffeine, Ascorbic acid, Extended drug release upto 24 h [261]

and 5-fluorouracil

Bioadhesive vaginal Fluconazole Delayed release with T80 17.4 h [262]

tablet
Dry powder inhaler Rifampicin and Sustained release at pulmonary region, upto 12 h for [263]
Rifabutin
rifampicin and up to 96 h for rifabutin
Alginate Matrix Tablet Metronidazole Effect of particle size of drug, additive used, and pH of [244]
medium was evaluated on drug release
Microspheres Blue dextran Extended drug release upto 24 h [245]

Pellets Theophylline Incorporation of Ca salt prolong the drug release [246]

Nanoparticles Cisplatin Folate conjugation provide selectively taken up by HNE-1 [247]

cells and Hep-2 cells
Pectin Colon specific Methotrexate Microparticles were prepared by ion gelation method [250]
microparticles
 Nanoparticles Diclofenac sodium Nanoparticles were able to release the drug for prolonged [264]
period of time
Pectin coated Vitamin C Significant improvement in permeation [265]
liposome
Guar gum Colon Tablet Metronidazole More availability of drug at colon [252]

Folic acid Methotrexate Enhanced uptake of delivery systems by colorectal cancer [266]
conjugated cells
nanoparticles
Nanoaggregates Isoniazid and Formulations shows enhanced local action due to sustained [267]
Rifampicin
release
Hydrogel Rifampicin Enhance mucoadhesion thus better efficacy [268]

Starch Microspheres Oregano essential oil High antioxidant activity values and stability [257]

Microparticles Curcumin Enhance stability against photodegradation and chemical [258]

oxidation

Nanoparticles CG-1521 (histone Decrease release rate of CG-1521 allowing remarkable [259]
deacetylase inhibitor)
cytotoxicity against MCF-7 breast cancer
Polysaccharides as emulsion stabilizers
The amphiphilic nature of chemically modified polysaccharides causes their adsorption at the
interface of oil and aqueous solvents that results in the stabilization of the emulsion [269]. This
property of polysaccharides proved highly beneficial for the delivery of lipophilic or non-polar
therapeutics at their target site [270]. As such, the native cellulose does not offer emulsion
stabilization due to its non-solubility in water. The chemically modified cellulose not only
improves its aqueous solubility but also affords the stabilization of the emulsion [271]. The
large size of polysaccharides slows down their adsorption process compared to the small sized
surface-active agents. Mainly, the polysaccharide-based emulsifiers mainly base on pectins,
gum arabic, galactomannans, and cellulose. Cellulose and starch promote the emulsion
stabilization only after their chemical modification however; the polysaccharides such as gum
arabic and pectins endowed with covalently linked glycoproteins possess intrinsic ability for
the stabilization of the emulsion. In addition, the polysaccharides such as xanthan gum,
carrageenan, alginates, hyaluronan, chitosan, and alginates that display trivial interfacial
activity offer the eulsion stabilization via thickening, gelling, and structuring [272]. The
structural relationship between chitin-based nanomaterials to that of cellulose results in a
similar amphiphilic behavior for potential applications as stabilizers of oil-in-water Pickering
emulsion. Starch microgranules demonstrate similar applications however; the nanocrystals
and nanospheres of starch exhibit a limited stabilization of the emulsion [273]. Yan et al. 2019
reported the stabilization of Pickering emulsions droplets by nanocrystals of bacterial cellulose
for hydrophobic drug delivery of Alfacalcidol. The irreversible adsorption of bacterial cellulose
nanocrystals at the oil-water interface of Pickering emulsions prevented the coalescence of the
droplets. The emulsion showed Ostwald ripening in the alginate solution. The interfacial
assembly of the amphiphilic bacterial cellulose nanocrystals and the hydrogel shells of the
alginate beads generated by the external gelation led to the achievement of efficient loading
and a controlled release of Alfacalcidol. The release mechanism of Alfacalcidol from the
composite beads followed non-Fickian transport. The alginate composite beads demonstrated
minimal toxicity that further proved beneficial for drug delivery applications. Koshani et al.
2021 presented the lipophilic drug delivery applications via natural emulgel obtained from
dialdehyde cellulose crosslinked with chitosan. The delivery of the lipophilic compound β-
carotene occurred using an embedded oil-in-water emulsion. The lipophilic β-carotene loaded
in the oil-phase showed 20% release in stomach after passing safely through the oral cavity.
Furthermore, 50% of β-carotene released in the intestines after 4h in the presence of emulgel
thereby indicating its application as oral delivery vehicle [274].
Clinical trials on Polysaccharide based drug delivery systems
Riedl et al. (1993) performed phase I clinical trials on the dextran-conjugated doxorubicin on
13 patients at a starting dose of 40 mg/m2 that led to the development of WHO grade IV
thrombocytopenia in 2/2 patients. Whereas, the WHO grade IV hepatotoxicity, and WHO grade
III cardiotoxicity appeared in patients with preexisting heart ailments. Lowering of the dose to
20 mg/m2 further decreased the existence of thrombocytopenia. However, the hepatotoxicity
persisted. Further reducing the dose to 12.5 mg/m2 caused marked reduction in the malignancy
fibrous histiocytoma for up to 4 months [275]. Soepenberg et al. (2005) performed phase I
clinical trials on DE-310, a camptothecin analog, and a carboxymethyldextran polyalcohol
carrier, in the patients with advanced solid tumors. The DE-301 drug delivery system
reportedly released DX-8951 drug slowly, while maintaining a sustained release. This
prolonged the drug exposure at its deliberated tumor site. Some patients showed partial-to-
complete remission of metastatic adenocarcinoma at dose 7.5 mg/ m2 [276]. Kim et al. (2006)
conducted phase II clinical trials on holmium 166/ chitosan complex for the effective treatment
of hepatocellular carcinoma. The percutaneous administration of the nanosystem caused a
complete tumor necrosis in 31/40 patients after 2 months period. However, a long-term follow-
up period indicated recurring of tumor in 28 patients. The polysaccharide based drug delivery
system proved beneficial for the treatment of small hepatocellular carcinoma by performing
local ablative procedure [277]. Pinnix et al. (2012) performed single-blind randomized phase
III clinical trials on topical hyaluronic acid after adjuvant radiotherapy for breast cancer. The
topical hyaluronic based gel did not proved effective for the treatment of grade 2 dermatitis
following radiotherapy [278]. Pritchard et al. (2016) reported phase II clinical trials on
oligosaccharide polymer therapy for modification of mucus barrier of COPD. The binding of
the oligosaccharide caused alteration in the surface charge, porosity, and 3-D mucin networks
in sputum of patients with cystic fibrosis, and its inhalation in patients caused effective
deposition in lungs and altered the viscoelasticity of the cystic fibrosis sputum [279].
Conclusion and Future perspectives
The polysaccharide based drug-delivery vehicles traversed a long journey for the controlled
release of pharmaceuticals at the target site with minimized ensuing side effects caused by the
customary delivery vectors. The biodegradability and trivial immunogenicity of the
polysaccharide-based drug delivery vehicles makes them the material of the future. The
controlled release profile offers improved drug pharmacokinetics thereby leading to
ameliorated local action, and effectivity. As such, the polysaccharides present the first-in-class
drug delivery system ‘Novochizol’ for the delivery of COVID-19 drugs. The system comprises
of biodegradable and biocompatible chitosan nanoparticles that strongly adhere to the lung
epithelium and offers a sustained drug-release. Similarly, the recent discovery of helical V-
amylose as advanced drug delivery system further validated the precedence of polysaccharides
as drug delivery vehicles. The helical morphology of V-amylose offers drug encapsulation in
the helix groves while interacting with the functional head groups. This system proved highly
advantageous for the delivery of indomethacin, diclofenac, and aspirin with enhanced gastric
tolerance. The conjugation of polysaccharides with metal nanoparticles with unique
physicochemical profile in the form of optical, electronic, magnetic, and surface properties
provide nanoprobes that present a sturdy candidature in bioimaging of the effected site, while
delivery the cargo pharmaceutical at the same time. The development of multicompartmental
microspheres based on polysaccharides revolutionized bioengineering and multi-drug delivery
with high precision. The coaxial electrospun fiber membranes based on polysaccharides
transformed the plant grafting techniques and effectively managed the plant tissue injury due
to their high mechanical and tensile strength. The biological phenomenon such as wood
degradation by brown-rot fungi led to the development of bioinspired, core shell cellulose
microparticles for the light-triggered release of anticancer drugs. Furthermore, the stabilization
of Pickering emulsions by chemically modified polysaccharides play a significant role in the
lipophilic drug delivery applications, and targeted delivery of various pharmaceuticals and
bioactive ingredients.
Despite several benefits, the polysaccharide-based formulations suffer limitations such as
susceptibility towards microbial contamination, uncontrolled hydration rate, and reduced
viscosity during storage. To overcome these limitations, it mandates the modification of natural
polysaccharides via cross-linking, grafting, and blending with natural and synthetic polymers
to improve their physicochemical profile. Similarly, the limited knowledge about the
mechanism of drug release by polysaccharides, and permeation enhancement decelerates the
progressive developments in polysaccharide-based drug delivery systems.

Conflict of Interest: The authors have no conflict of interest

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Revised Manuscript (Text with Changes marked) Click here to view linked References

Keywords: Polysaccharides, Drug delivery, Biocompatible.

Abstract
The polysaccharide-based advanced drug delivery system owing to their biocompatibility, ability
to encapsulate the drug molecules in their interspaces, and ability to achieve a controlled release
of the cargo drug molecules result in improved drug pharmacokinetics. The drug-loaded
polysaccharides possess ability to evade the multidrug-resistant microbial efflux pumps by
aggregation effect, whereas the drug loaded polysaccharide-fabricated metal nanoparticles present
an exceptional candidature for effectively transporting the drug molecules across the membrane
barriers while enabling the theranostic applications at the same time. The biodegradability of
polysaccharide based drug delivery systems ensure a sustained release of the encapsulated drug
molecules, which minimizes the side effects caused by a burst release of the cargo therapeutics.
These drug delivery systems proved highly beneficial for the NSAIDs that otherwise manifest
ulcerogenic effect in the gastrointestinal tract. The large surface area of polysaccharides further
provide a higher drug-loading capacity, which maintains the optimal concentration of the cargo
drug at the target sites. The emerging applications of biodegradable polysaccharides in the
designing of multicompartmental microspheres revolutionized tissue engineering, multi drug
delivery, and cell culturing technologies. The present review deals with the current-status of
polysaccharides as advanced drug delivery systems.
Introduction
Polysaccharides comprise of repeated mono- or disaccharide units connected via enzyme-
susceptible glycosidic bonds, which support their applications as controlled release drug carriers.
Their remarkable physicochemical and physiological properties such as biocompatibility,
biodegradability and low immunogenicity [1-4] further validate the drug delivery applications.
Usually, such natural polysaccharides are easily available from the plant, animals and microbes.
Such polysaccharides possess various physicochemical properties such as being neutral or having
positive or negative charge, being able to have linear or branched molecular structure, and their
molecular weight can vary from a few hundred to several thousand Daltons [5-7]. Due to these
properties, the polysaccharides have considerable impact on the biodistribution of carrier drug
molecules in-vivo [8, 9].
Numerous polysaccharides could even adhere to the layer of mucus, which covers epithelial
surfaces throughout the body. Thus, the polysaccharide based carrier systems have extended in
vivo residence time in gastrointestinal (GI) tract, thereby increasing drug bioavailability [10-14].
Cationic polysaccharides such as chitosan and its derivatives have the capacity to open the tight
interconnections among epithelial cells, thereby increased hydrophilic drug permeability through
mucus membranes [15-20].
The polysaccharides possess an inherent ability to recognize specific receptors, which over-
express on the surface of morbid tissues. As such, hyaluronic acid specifically binds to the over-
expressed CD44 receptor of several tumor cells [21]. In addition, pullulan reportedly possesses a
high specificity towards asialoglycoprotein receptors that express at the surface hepatocytes [22].
The unique binding of these polysaccharides with certain receptors permits a rational designing of
novel carriers, which selectively deliver the cargo drugs by means of receptor-mediated
endocytosis [23-26].
Besides, the polysaccharides present extensive applications as multi drug-delivery systems,
In this review, we present a comprehensive survey of the advanced applications of Polysaccharides
in drug delivery and other biomedical applications and the various factors that determine the
efficacy of these applications.
Physicochemical Factors
The alterations and chemical modifications of the functional head groups such as –COOH, -NH2,
and -OH on the polysaccharide structures led to the generation of polysaccharide derivatives with
distinct properties for specific applications. Reportedly, the sulfonation of Pullulan ameliorates its
anticoagulant activity compared to the non-sulphated counterpart. Whereas the thiolation of
chitosan significantly improves its mucoadhesive properties compared to the non-thiolated
counterpart [27, 28] owing to the formation of tight covalent bonds with cysteine-rich mucus
glycoprotein subdomains by the former [29, 30].
The interactions with functional head groups on polysaccharides enables the incorporation of
therapeutic drugs into the main chain through covalent bonds or electrostatic interactions followed
by subsequent release of the incorporated drug at target site under a suitable stimuli [31, 32].
Similarly, the amphiphilic derivatives of polysaccharides prepared by tethering the hydrophobic
moieties to the parent chain possess self-assembly properties in physiological settings and present
applications for the delivery of hydrophobic drug molecules such as paclitaxel to the target cells
[33-36].
Zeta potential also plays an important role in the drug delivery applications by polysaccharides by
influencing the interactions of polysaccharide nanosystems with proteins and cells [37]. The
factors that generate a net charge on the surface of polysaccharide nanocarrier contribute towards
the production of a high zeta potential. The dissociation of ionogenic surface group or adsorbed
molecules, and the presence of other ions in parent solvent or on the surface of the molecule offer
a significant contribution towards the zeta potential of non-ionogenic polysaccharides. However,
when the aqueous medium has no other electrolytes, the hydroxide ions adsorb on the surface of
polysaccharide resulting in an overall negative surface load [38, 39].
The pH value of the medium in addition to the ionic strength, particle size and particle density
considerably influence the zeta potential [40-42]. Acidic pH promotes the adsorption of protons
due to increasing concentration (the zeta potential increases) while a reverse effect takes place at
basic pH due to the elevated concentration of hydroxide ions. At a certain pH level, the zeta
potential may become zero, leading to instability in the colloids and accumulation of particles.
Increasing electrolyte rates in the parent medium usually result in the shielding of electrical
charges. This result in to the compression of the electrical double layer that contributes to less
electrostatic repulsion and colloid coagulation [43-45].
The phosphorylated chitosan-based micelles have been studied for their effect on mucosal drug
delivery during the change in zeta potential. On contacting the alkaline phosphatase (cell surface
glycoproteins found in many organs such as the intestine, the lungs and the vagina), the
phosphorylated micelles undergo a split off to make the zeta potential from negative to positive or
neutral [46-48]. An initial negatively charged surface enables the micelles to resist the binding of
polysaccharide to negative charged components of the mucus and diffuse through the layer of the
mucus. Whereas, a subsequent positive charge enhances the contact of polysaccharide with mucus
and cell membranes thereby preventing the back diffusion, cellular premising and internalisation
[49, 50].
Biodegradable polysaccharides or biopolymer-based nanomaterials disintegrate during their
intended function in physiological settings [51]. These polymers degrade in situ to generate the
natural by-products such as water, carbon dioxide, and small organic molecules [52]. The
backbone of these polysaccharides include functional groups of ester, amide, and ether that
undergo enzymatic degradation in physiological environment [53]. Their structure
and composition dictates the mechanisms of their degradation [54-56].
The backbone of polymeric materials consists of chemical bonds including polyesters,
polyamides, and polyanhydrides that offer numerous implementations. The polymeric materials
composed of carbohydrates consists of large chains of monosaccharide units that by hydrolysis
produce the monosaccharide portion or the oligosaccharide component. Their constructions
vary from linear to highly branched polymers. Minor differences in polysaccharide molecules can
lead to a substantial difference in the properties [57]. As such, even the minor stereochemical
differences in starch and cellulose result dramatically different functions. Click chemistry and
radical polymerization techniques bind several polymers to the cellulose backbone due to the
presence of several functional head groups on the polymeric backbone. Especially, the green
polysaccharides have been of recent interest because their biodegradability and the materials based
on these polysaccharides are ideal for absorption and subsequent removal from the body and the
systemic circulation. Interestingly, the 500 odd species of bacteria in the intestinal tract make this
environment an exceptional microbial ecosystem. The gut microbiota conduct a simple series of
biochemical processes involving starch breakdown, vitamin synthesis, and fermentation, while the
polysaccharide oxidation happens in the intestines [58]. A great deal of research has been done
focused on alkaline polysaccharide degradation based primarily on 100 ºC or less temperatures to
evaluate processes of degradation, kinetics of degradation, and interactions between structural
composition and environment [59-63].
The polysaccharides do not convert into acids at low temperatures, while in an alkaline solution,
both the starch and cellulose thermochemically degrade to water-soluble compounds [64, 65].
These properties support the colon-targeted release of the cargo drug molecules and prevent their
premature release in the acidic pH of the stomach [66].
Mainly, the alkaline degradation of starch provides products such as starch and cellulose, in
addition to small organic compounds such as acetic acid, formic acid, lactic acid, glycolic acid, 2-
hydroxyvaleric acid, and 2-hydroxybutyric acid. The second-order kinetics with the Arrhenius
equation for reactivating energy of 165 kJmol-1 explains the decay of starch and cellulose in
alkaline solution [67]. The thermal decomposition investigations of polysaccharides calculated
utilizing a slit viscometer for sodium alginate, carrageenan, and carboxymethyl cellulose (CMC)
was reported with results indicating alginate to be much less robust than CMC and carrageenan
[68-69]. The activation energy for carrageenan reportedly appeared as 104 kJmol-1, while alginate
displayed 50.7 kJmol-1 activation energy, with CMC to be 79.9 kJmol-1 [70].
BIOTOLERANCE
A major attribute to PS-based nanomaterials, in addition to their biocompatibility, is their
physiological tolerance towards the live cells. Polysaccharides reportedly exhibit strong propensity
to aggregate based on the concentration of hydroxyl or amino groups involved in hydrogen
bonding within the macromolecules. The reversible interactions primarily happen at increased
concentrations of the polysaccharide and decreases again after the sample dilution. Further, the
polyelectrolyte concentration significantly effects the multilayered structure and the density of the
polysaccharide materials. Reportedly, the polysaccharide concentrations between 0.1% and
0.5% play a significant role in the construction of multilayered structures [71-75]. The charge on
polysaccharide surface determine the aggregation of their colloidal solutions where different
surface charges are liable for multiple polysaccharide behaviors. The pH and the ionic intensity of
the media further influence ionization levels of the polysaccharides, and hence the complex
formation and phase segregation of low polyelectrolytes are generally associated
with polysaccharide-based nanomaterials [76].
Effect of pH
Within the last few decades, the pH-dependent swelling-shrinking induced behavior resulted in the
formation of new polysaccharide NPs that received significant interest in drug delivery [77, 78].
The stimuli-responsive therapeutics release rely on different interactions induced by
the aqueous property, polymeric backbone, and pharmaceutical structural composition [79-82].
Researchers, therefore, evaluated the swelling behavior of polysaccharide NPs in buffer solutions
of various pH values and reported that the swelling efficiency increased with pH value, indicating
clearly that polysaccharides NPs present a good candidature for a drug carrier with the ability to
sense variation in surrounding pH. Several polysaccharides exhibit an
outstanding tolerance towards wide pH conditions, salt concentrations, while displaying an
excellent thermal stability [83]. Depending on the gastrointestinal (GI) secretions, the rationally
designed sustained-release formulations of polysaccharides depend on pH of the environment, and
cationic charge [84-85]. As such, the carboxy groups present on the polysaccharide offered pH-
sensitivity to the dextran-based NPs. Zhang and coworkers documented unique pH- and aqueous-
force-sensitive hydrogel membranes wherein pH-dependent swelling appeared in the acidic side
chains of the polysaccharides [86-87]. More recently, by grafting synthetic poly(acrylic acid)
copolymer (D-A copolymer) on dextran, the researchers designed an altered copolymer that
displayed biotolerance, biodegradability, biocompatibility and pH-sensitivity. This
polysaccharide-based system effectively delivered Ibuprofen in the phosphate buffer solution
(PBS) at pH 2.0 and pH 7.4. The findings further indicated the pH-responsiveness of copolymer,
which enhanced with increase in the molar ratio of AA/dextran [88].
Effect of ionic strength
Another variable that affects the particle size is the ionic strength of the solvent and the
concentration gradient that plays a significant role in designing the materials with drug delivery
applications [89]. The alternative crystalline structure and amorphous cellulose structure
(contributing to stability and plasticity) offer a lower rigidity to the resulting nanofibrils at high
ionic strength [90]. At moderate ionic strength, the polysaccharides-based nanomaterials promote
stem cell replication without inducing cytotoxicity or inflammatory effects in vivo [91].
Polysaccharide based nanomaterials are often responsible for in vitro anti-inflammatory effects on
human keratinocytes [92]. One of the critical elements to evaluate the tolerance of the immune
system towards polysaccharide-based drug delivery systems is through the evaluation of dendritic
cells (DCs), which are the central inherent immune cells that regulate the immune response to
specific nanomaterials [93]. DCs can also promote immune resistance by producing ILT 3, ILT4,
indoleamine-dioxygenase (IDO)-1, and cytokine IL-10. Inflammatory and regulatory populations
of T cells may also contribute to the regulation of inflammatory diseases. The DCS are the primary
goal in diagnosis with tumors, infectious disorders, persistent inflammatory problems, implant
recognition, and wound repair [94-96]. The polysaccharide-based nanomaterials reportedly induce
adequate immune tolerance by recruiting the differential human DCs that can down-regulate Th1
and Th17 cells and up-regulate Th2 and Treg in vitro [97-99].
THERANOSTICS
The application of biodegradable polysaccharides for an effective drug delivery and bioimaging
of the drug activity in the target morbid tissues is becoming rapidly desirable. The biodegradable
natural polymers based on polysaccharides present extensive applications as tablet binders and
viscosity liquid or emulsifying agents. The polysaccharides used as coating agents ensure the
avoidance of an undesirable product flavor, enhancement in medication safety as well as
improvements in pharmaceutical volume, and release rate [100]. The short half-life of deliberated
pharmaceuticals requires multiple injections or doses, which continues to raise adverse effects and
medication expenses. In the case of poor patient adherence, multiple dosing is also problematic.
To solve these issues, the process of drug delivery to patients improved by adding biodegradable
polymers for medication encapsulation [101]. The crosslinking of the cargo pharmaceutical with
biodegradable polymer releases on a continuous or regulated basis from the encapsulating
polysaccharide. Mainly, the extent of crosslinking in the encapsulating polysaccharide material
determines the release profile of cargo drug molecules. The placement of the cargo pharmaceutical
into a hydrogel such as CMC polymer generates several pores created by hydrolysis and other
ways of degradation, which allows a controlled release of the cargo drug [102].
Polysaccharide-based contrast agent
For engineered polysaccharide-based NPs as theranostic nanomaterials, the efficacy depends on
the route of operation, retention period and the form of imaging and therapy. The selected
polysaccharides and their key characteristics, including the size, and structure poses a significant
impact on the theranostic applications. The amphiphilic polysaccharides containing stimuli-labile
linkers or hydrophobic moieties serve as a useful theranostic material [103]. Bio-
reducible disulfide connectivity cleavable in the intracellular environment prepared by chemical
modification of Carboxymethyl dextran (CMD) to lithocholic acid presented interesting
theranostic applications [104]. In another study, doxorubicin released in PBS with 10 mm of
glutathione, a tripeptide that intracellularly reduces disulfide bond in selective and robust
polynomial nanomaterials [105]. The reported nanomaterial improved the biodistribution of the
cargo drug in tumor cells as indicated in the labelling experiments. As a result, antitumor efficacy
in vivo of DOX-loaded NPs was considerably higher in comparison to reduction-insensitive NPs
of CMD [106]. Furthermore, cucurbit [6] uril-conjugated to (CB [6]-hyaluronate)
was developed as a model of the desired imaging system (Jung, Park et al. 2011). The decoration
of this complex framework with FITC-spermidine (spmd) and/or the formyl-peptide receptor-like
1 (FPRL1) resulted in the formation of (FITC-spmd and/or peptide-spmd)@CB[6]-HA
nanosystem used effectively to image its target-specific delivery in human breast adenocarcinoma
cells (FPRL1 / MCF-7) with elevated Ca2+ and phosphorus-extracellular signal-regulating kinase
(pERK) [107]. Qu et al. 2021 reported advanced delivery system based on the nanocellulose-
containing microparticles that offered ROS-trigger release of doxorubicin. The microparticles
consisted of light-sensitive shell containing Indocyanine green, which generated ROS on near
infrared laser irradiation, eventually causing the degradation of cellulose nanocrystals present in
the microparticles [108]. This bioinspired system based on ROS-mediated wood degradation by
brown-rot fungi possessed minimal toxicity and non-immunogenicity that further validated its drug
delivery applications. Further advancements led to Gas-shearing fabrication of
multicompartmental microspheres obtained from water-soluble cellulose acetate, ethyl-cellulose,
and cellulose-acetate-phthalate. The utility of biodegradable polysaccharides instead of the oils
and surfactants for the generation of monodisperse multicompartmental microspheres led to the
achievement of cytocompatibility by the microparticles. In addition, the oil-free gas-shearing
process allowed the design of microparticles up to eight compartments with a precise control over
the properties of each of these compartments. These microspheres offered applications in
biomedical engineering due to their ability to carry multiple materials in separate phases. These
microparticles presented applications as multidrug delivery vehicles, multitarget detection,
multienzyme tandem reactions, and in cell culturing technologies. The robust candidature of these
microparticles in tissue engineering resolves the key challenges associated with cellular delivery
in the current bioengineering paradigm [109]. The recent fabrication of coaxial electrospun core-
shell fibers based on cellulose acetate offer a sustained release of the biological compounds
necessary for promoting plant growth, and promote tissue healing in plants. The impregnation of
these fibers with polyurethane provides mechanical strength and enhances the modulus of
elasticity that further result in the development of plant wound dressings. Initially, the core-shell
fibers displayed 50% release of the encapsulated material in 72h, followed by a slower release that
occurred mainly due to the hydrophobic nature of cellulose acetate. This release profile however
discouraged the sustained release application of core shell fibers. The hydrophilicity of cellulose
acetate and hydrophobicity of coaxial polyurethane caused the loading of cargo drug in the latter
due to the poor affinity of the drug with water. Notably, the encapsulated drug displayed two-stage
release kinetics from the cellulose acetate-polyurethane coaxial electrospun fibers [110].
Superparamagnetic iron oxide nanoparticles possess characteristic magnetic properties for
bioimaging applications. Their coating with polysaccharides provide robust drug delivery
materials with theranostic applications [111, 112]. Furthermore, as an innovative method for
achieving a controlled drug delivery and bioimaging applications, superparamagnetic iron oxide
nanoparticles coated with hyaluronan (HA) (HA-FeO). The target cancer cells rapidly uptake HA-
FeO nanosystem on incubation for 24h [113], and HA-FeO internalization into the cancerous cells
was far higher than NPs without HA fabrication. Notably, the high magnetic relaxation and
increased utilization of HA-FeO promote cancerous cell imaging. The anchoring of DOX via an
acid-responsive linker to the NPs further promoted a controlled release of the drug. DOX-HA-FeO
system was far more potent than free DOX in offering therapeutic properties against the multidrug-
resistant cancer cells [114]. Choi et al. 2010, identified the simultaneous delivery platform for the
gene/drug, and tumor by using chitosan functionalized magnetic graphene (CMG). The
nanosystem provided a robust candidature as T2 contrast-improving agent as indicated by the
phantom tube experiments and ex vivo MRI. As measured by the WST method, CMGs
concentrated mostly on the tumor cells, as demonstrated by distribution studies and MRI [115].
Heparin-folic-IR-780 (HF-IR-780) multifunctional NPs synthesized by self-assembly through an
ultrasonic sound method specifically targeted the tumor cells while providing the bioimaging
applications. Assays on in vitro cell viability and photothermal in vivo therapy show a mixture of
HF-IR-780 NPs with 808 nm laser radiation in the shape of MCF-7 or xenograft MCF-6 cell tumors
[116]. Glycolated chitosan based Bcl-2 siRNA complex provided applications in gene therapy in
addition to providing theranostic applications for the imaging of solid tumors. Further, the
polysaccharide-based nanomaterial assisted the targeted delivery of doxorubicin to the target
cancer cells [117].
Polysaccharide-based drug delivery systems
The differential pH gradient between the tumor and healthy tissues, as well as between cytoplasm
and endosome serves as essential stimuli for smart drug delivery applications. The four specific
approaches utilized to design the pharmaceutical carriers include drug conjugated to the
polysaccharide, entrapment of therapeutics through in aerogels and hydrogels, formulation of
drug-loaded polysaccharide nanoparticles (NPs) through the self-assembly. Figure 1 highlights the
various types of interactions between the drug molecule and polysaccharides.
 Figure 1. The types of interactions between the polysaccharides and drug molecules
MODIFICATION OF POLYSACCHARIDES
Physical Interactions
Polysaccharide molecule containing functional head groups on their surface undergoe chemical
modification for conjugating with the desired drug molecules [118]. Specifically, the -OH group
present on the polysaccharide undergoes esterification or etherification with acylating and
alkylating agents respectively [119-120]. This group undergoes further oxidation to –COOH and
–CHO groups in the presence of a suitable oxidizing agent that further extends the chances of
conjugation with a diverse range of functional groups on the cargo molecule. The –COOH group
and –NH2 functionalities in polysaccharides undergo amidation, hydrazone formation, and Schiff
base modification to conjugate with the cargo drug molecules [121-123]. Typically, the formation
of polysaccharide gel requires a chemical or physical cross-linking of the polysaccharide for
encapsulating the therapeutic molecules [124-127]. Mainly, the physical cross-linking of
polysaccharides involves simpler preparation protocols devoid of chemical reagents [128]. The
polysaccharides containing –COOH or –NH2 groups reportedly undergo ion complexation to
generate the physically cross-linked nanohydrogels with myriad applications as drug delivery
vehicles [129]. Typically, the anionic polysaccharides generate hydrogels by interacting with metal
cations, while the cationic polyglucosamines interact with multivalent metal anions [130-131].
Similarly, the negatively charged alginic acid displays cross-linking interactions with CaCl2,
whereas the positively charged chitosan readily interacts with sodium tri-polyphosphate [132-
134]. Notably, the carrageenan polysaccharides contain sulfonate group along their backbone that
serve as a site for cross-linking with metal ions as well as cationic polymers such as chitosan [135-
137].
The interactions between the dissimilarly charged polymers result in the formation of
polyelectrolyte complex [138]. Mainly, the ionic interactions in the polyelectrolytes exhibit a
superior strength compared to the van der Waals forces and hydrogen bonding interactions [139].
The negatively charged polysaccharides including hyaluronic acid, pectin, xanthan,
carboxymethyl cellulose, alginic acid, and chondroitin sulfate form the polyelectrolytes [140-142].
(Boddohi et al. 2009; Wu et al. 2020; Potas et al. 2020). In addition, the proteins such as albumin,
gelatin, collagen, keratin, and synthetic polyacrylic acids reportedly generate polyelectrolytes
[143].
Hydrophobic interactions result in the physical cross-linking of polysaccharides for maintaining
the structure and morphology. The anchoring of hydrophobic groups to the polysaccharide chain
lower the water solubility and promote hydrophobic drug delivery [144]. The amphiphilic
copolymers prepared by entrenching the hydrophilic polymeric backbone with hydrophobic
structures, orient themselves to achieve a minimum free energy state, while the hydrophobic
portion disengage from the aqueous environment thereby forming core shell structure of polymeric
micelles [145]. The structures containing hydrophilic outer shell enclosing the hydrophobic
interior serve as carrier for hydrophobic drug molecules [146]. The modification of
polysaccharides with long chain fatty acids such as palmitic acid, stearic acid, linoleic acid,
linolenic acid, and hexanoic acid result in the generation of polymeric micelles [147-148].
Similarly, the conjugation of polysaccharides to hydrophobic polymers such as poly
(ɛcaprolactone), poly (isobutyl cyanoacrylate), poly (ethylene glycol) derivatives, and pluronic
copolymers generated the desired core-shell drug delivery systems with hydrophobic core and
hydrophilic shell [149]. Nevertheless, the presence of polar groups such as –OH, -COOH, -NH2 in
polysaccharides participate in hydrogen bonding interactions that play a critical role in drug
delivery applications. The polysaccharides such as chitosan forms hydrogen bonds at pH > 5,
whereas it requires low temperature and pH to form hydrogen bonding in agarose [150]. Similarly,
the synthetic polysaccharide carboxymethyl cellulose demonstrates pH sensitive hydrogen
bonding interactions, which form the basis of drug delivery applications in these polymeric
systems [151].
Chemical modifications
The chemical modification of polysaccharides led to their conjugation with drug molecules via
functional head groups through the covalent bonds. These chemical modifications followed by a
subsequent conjugation mainly occur via nucleophilic replacement of the saccharide oxygen by
heteroatomic nucleophiles. Typically, a saccharide electrophile possesses lower reactivity towards
the nucleophilic substitution compared to the other hydrocarbon-derived molecules [152]. The
destabilization of carbocation generated at the primary or secondary position due to the presence
of surrounding electron withdrawing –OH groups increases the difficulty of SN1 reaction at the
primary and secondary positions, as compared to the SN2 reactions at the same position [153].
The bulkiness of the alkoxy and acyloxy substituents further lower the reactivity of saccharide-
derived electrophiles toward SN2 reactions [154]. Especially, the higher stability of the chair
conformation of the six-membered saccharide ring and the presence of multiple equatorial
substituents makes it difficult for the completion of an SN2 attack the secondary position of the
target saccharide [155]. Mechanistically, the formation of SN2 transition state involves changes in
the ring conformation for accommodating the attacking nucleophile, and the leaving group around
the central carbon. However, the highly stabilized chair conformation refuses to undergo these
conformational changes as it results in less favored strained conformation [156].
The replacement of primary and secondary –OH groups in saccharide molecules with a good
leaving group improves the susceptibility of electrophilic carbon towards the nucleophilic attack.
Mainly, the halide ions, and the less reactive functional groups such as phosphonate and sulfonate
prove better leaving groups at the primary position. While the groups such as triflates and epoxides
serve as better leaving groups at the secondary position. The nucleophilic reaction by a saccharide
nucleophile through the ‘O’ atom result in the acylation or alkylation of the polysaccharide,
whereas the nucleophilic attack on polysaccharide molecules by alcohols or carboxylates for the
formation of ether and esters occur less commonly [157]. The esterification of polysaccharides
occurs preferably via Mitsunobu reaction, which incorporates an in situ activation of the -OH
group by phosphonium leaving group, where the attacking nucleophile facilitates its departure
[158]. The high-yielding, regioselective Mitsunobu reactions mainly occur at the primary position
of unprotected saccharide units [159]. Amine group acts as neutral nucleophile for modifying the
polysaccharide with alkyl chains. Preferably, the monovalent properties of the azide nucleophiles
prevent the multiple side reactions or cross linking of the parent polysaccharide. The azide
functionalization of polysaccharides proves highly beneficial for their click conjugation to the drug
molecules or biomolecules bearing a propargyl substituent [160]. The click conjugation of
polysaccharides with desirable drug molecules via strong triazole spacer improves the in vivo
stability and the pharmacokinetics of the drug delivery system [161-162]. Particularly, the click
conjugation presents extensive applications in molecular medicine where the cargo therapeutics
bind with desired biomolecules including polysaccharides, antigens, nucleic acid sequence,
mRNA, and peptides [163]. Likewise, the thiols participate in nucleophilic substitution with
polysaccharide rings that contain halides as leaving group.
 NH(CH 2)7CH 3 OH OH OH
O
O O O
O PPh3 / CBr 4
O O
O OR NaN 3 / DMF
H 3C(H 2C) 7HN O OH OH
OH OH
O O N3
O Amidation Ugi reaction
NH O
NC
OH OH EDC/ CMPI O
CH 3(CH 2)7NH 2
OH OH
Esterification HCHO/ CH 3(CH 2)7NH 2
Azide formation
(ROH/ catalyst) OH OH
OH O O OH OH
O HO
O O O
O HO O OH O
O
OH OH
OH O
O Polysaccharide O
O OH O
OH OH
Reductive
Amination
Oxidation Sulfation
(NaIO4) O OH (ClSO3H/ formamide)
O
O OH
O OH
O
O HH
O O O O
HH
NH 2R O
O O
O OH NaCNBH 3 O OH OH OSO3H

O O
O O
HH
N N HN NH
R R R R

Figure 2. Chemical modifications on polysaccharides

Figure 2. Illustrates the various chemical modifications done on polysaccharides at the free –OH,
and –COOH groups. The oxidation of polysaccharides at the –OH groups on C2/ C3 position to
yield aldehyde groups causes a faster degradation in physiological background when used as
controlled drug delivery carriers. The conversion of hydroxyl substituent to aldehyde groups
provide a rotational freedom to the parent saccharide units, however it requires precautions such
as light exclusion to prevent the occurrence of any side-reactions, in addition to limiting the
concentration of the oxidant in order to achieve a controlled oxidation of alginate [164]. Notably,
the oxidized polysaccharide completely degrades at the physiological pH = 7.4 at 37 oC, thereby
making it an excellent drug delivery carrier [165]. The oxidation of polysaccharide units results in
the formation of reactive aldehyde groups, thereby encouraging further chemical modification by
reductive amination. The conversion takes place in the presence of suitable reducing agents that
selectively reduce the imine intermediate, over the starting aldehyde group [166]. The reductive
amination of polysaccharides with long chain alkyl amines provides amphiphilic properties to the
parent polysaccharide, and lower their surface tension for a better physiological absorption. This
drug delivery system ensures a better loading capacity of hydrophobic drug molecules for
achieving a controlled drug release profile. The structural similarity of sulfated polysaccharide
with anticoagulant heparin improves the blood compatibility of the test polysaccharide deliberated
for drug delivery applications [167]. The in vitro assay for appraising the coagulation of human
plasma in the presence of sulfated alginates suggested notable anticoagulant properties of the
polysaccharide by targeting the intrinsic coagulation pathways [168]. Similarly, the esterification
of polysaccharide acids with alkyl groups improves the hydrophobicity of the parent
polysaccharide. Furthermore, the synthesis of alginate bis-amides via Ugi reaction presents an
important modification of polysaccharides for their drug delivery applications.
Polysaccharide-drug conjugates
Numerous natural and synthetic water-soluble polymers reportedly exhibit conjugation with
therapeutic molecule through chemical conjugation [169]. Pharmacokinetic investigations of
drug-conjugating polysaccharides have documented the implications of natural and sustainable
polymers as robust drug delivery systems. In addition to the synthetic, water-soluble polymers, the
natural polymers such as dextran, chitosan, hyaluronic acid, and cellulose seem to have a
tremendous drug carrier potential [170]. Coupling of the hydrophobic doxorubicin (DOX) with the
acid-cleavable hydrazone bond generated DOX-chitosan nanoconjugates with pH-sensitive drug
release [171]. The study revealed that the chitosan-DOX conjugates with the acid-cleavable
hydrazone bond became stable at neutral pH and dissolved at pH 5.0, which made a significant
contribution to the eruption of DOX into HeLa cells. Prodrug NPs internalized rapidly to illustrate
its potential applications in tumor-targeted pharmaceutical materials, contributing to a substantial
accumulation and deposition of DOX in HeLa cells [172]. Simple carbohydrates, such as dextran
reportedly utilize in the recombination of medications. Bacterial strains, including Leuconostoc
and Streptococcus produce copious amounts of dextran polysaccharide, including the primary and
secondary categories of dextran that offers possible therapeutic conjugation regions with specific
methods [173-174]. Reportedly, the destroying the impact of free curcumin on cancerous cells
diminishes with time, whereas the cytostatic activity effects of curcumin-loaded chitosan NPs of
the same concentration range on MCF7 cells improved significantly in the incubation period.
Furthermore, the chemical tailoring of such materials offered selective and more efficient drug
delivery to tumors due to the predominant amine and hydroxyl groups on the chitosan framework
[175]. For the delivery of paclitaxel (PTX) and docetaxel (DTX), Skorik et al. used chitosan-based
NP as nanocarriers. The drug-charged succinyl and glutaryl chitosan NPs displayed a considerable
cytotoxicity towards the gastrointestinal cell lines and thus increased their anticancer activity
compared to free drugs. Due mainly to a tumor-homing ligand (3-carboxyphenylboronic acid), the
updated carboxymethyl chitosan-based NPs loaded with DOX demonstrated an increased
accumulation concentrations and penetration into tumor presenting mice with H22 lung
metastasis. This significantly reduced the mass of the H22 metastases lung tumor by further
infiltration and aggregation of NPs in the tumor site.
D-glucuronic acid repeats and D-N-acetilglucosamin disaccharide conjugate to generate
the hyaluronan (HA) by means of β-1,4- and β-1,3-glycosidic links [176]. The hyaluronate
framework comprises of hydroxy and carboxyl groups, which participate for the conjugation with
several drug molecules. Considering the steric hindrance and weak carboxyl reactivity, direct
conjugation could is not preferred [177-178]. HA derived products that have the functional head
groups such as hydrazine (-NH2-NH2-) improve the reactivity and drug conjugation efficacy. HA
derivatives that require carboxylic acids to be substituted and functionalized also display increased
drug loading with limited alteration in the polysaccharide structure [179]. Paclitaxel (PTX) was
elevated in loading and reduced product toxicity relative to free PTX in conjugations with HA-
deoxycholic acid coupled to bio-reducible cysteamine. The binding effects of the medication
retains even after a significant degree of replacement. Several methods reportedly cope with the
low solubility of HA in conventional organic solvents, which hampers cytotoxic conjugation
reactions [180]. Those methods include the use of combinations of polar solvents with water,
polyethylene dimethyl ether nanocomplexation and ion compositions of long-chain aliphatic
cations [181]. The application of HA-drug conjugates offer a selective targeting of the excessive
CD44 overexpressed receptors [182]. HA-conjugated products, including HA-mitomycin C, HA-
epirubicin, HA-butyrates, and HA-paclitaxel present robust applications in drug delivery. Notably,
the inhibitor of histone deacetylase demonstrated enhanced apoptosis activity, resulting in reduced
in vivo tumor load and inhibition of in vitro cell development on its conjugation with HA [183].
The usage of N, N'-dicyclohexylcarbodiimide (DCC), and cholic acid derivatives (Colic acid) have
modified sucrose and poly(d, l-lactic-co- glycolic acid) (PLSGA) through crosslink. This
represents an exciting development for a controlled system of drug delivery for medications with
low aqueous solubility [184]. Numerous uses featuring various composite hydrogels composed of
polysaccharides including chitin, nanocellulose and chitosan offered advanced pharmaceutical
delivery systems, enhanced regenerative medicine, tissue engineering, wound dressings, and water
purification sorbents [185]. Chitin composites can be generated in spherical nanogels, in
conjunction with rhodamine 123 dye that improved the drug distribution provides applications in
tissue engineering [186, 187]. The polysaccharides conjugated to folate, fluorescent functionalities
maintain an optimal drug loading and drug release profile and present potential applications for
gene therapy on specific positions, including cancerous cells [188]. Development of wound
treating products based on Pectin in the recent years combined with cellulose and micro fibrillated
cellulose offered promising results in vivo. The findings on animal models were encouraging, but
further experimental tests were required for clinically success. Pectin presents applications in
medicinal sprays as a drug carrier for the administration of drugs. The Pectin incorporated nasal
spray drug such as fentanyl that relieves pain in cancer and contributes to better chemotherapy
treatment [189]. Figure 3 depicts the main strategies for drug encapsulation by polysaccharides.
 Figure 3. Drug loading strategies by Polysaccharide nanoparticles
Drug retention in aerogel layer and hydrogels
Hydrogels represent 3-D hydrophilic, polymeric platforms, which hold potential preserve large
quantities of water or biological fluids. Aerogels are extremely porous and provide large internal
surfaces with exceptional drug delivery capabilities [190, 191]. Almost all of these gels are static
and brittle; however, polysaccharides form xerogels and they tend to generate transparent
hydrogels, which spontaneously shape interconnected polymers. The morphological and chemical
features of a gel rely on the consistency of the formulated aerogel. For the processing and
distribution of chemically stable hydrogels and aerogels, the utilization of hydrophilic
polysaccharides and their precursors offer selective delivery of therapeutics [192, 193]. The
association of a polyelectrolyte with an opposing multivalent ion by dynamic co-conservation
determines the properties of ionotropic hydrogels. Hydrogels are sensitive to different
environmental conditions including pH, ionic strength, and temperature that influence their
characteristics and morphology [194, 195]. In certain settings, it is feasible to provide a long-
lasting release for up to three months of nanofibrillar cellulose for long-term pharmaceutical
applications [196]. In an attempt to improve the structural strength and the swelling-deswelling
abilities of the polymer, engineered single networks to the hydrogel reduced the structural strength
to obtain the interpenetrating polymer (IPNs). The IPNs constitute of the interconnecting polymer
network formed by linking two different polysaccharides. In this context, gelatin-grafts-
polyaniline and carboxymethyl chitosan were prepared as injectable coordinating IPN hydrogels
with enhanced mechanical proprieties, crosslinked in physiological terms with oxidized dextran
via the Schiff base formation. The evaluation of hydrogels for in vivo biocompatibility
demonstrated a tremendous potential for drug and tissue development [197]. Alginate is a charged
biopolymer consisting of repetitive disaccharide units comprising of 1-4-linking β-D-mannuronic
acid and α-L-glucuronic acid organized in separate blocks or alternating blocks at different
proportions. Researchers have been able to establish advanced techniques for the distribution of
natural pharmaceutical medications with the use of ionic and covalent combinations to form
Alginate-based gels [198]. The redox-sensitive alginate offers applications in the construction of
hydrogels and nanogels using carbodiimide interconnection. Gels developed using redox-
degradable polymers dissolve to release the cargo medicinal product. The poly(diallyl
dimethylammonium chloride) (PDADMAC) conjugated with alginate provides temperature- and
pH-sensitive hydrogels in drug delivery applications. The pH behavior of the hydrogels implies
total swelling at pH 4, due to the ionization of the COOH groups in alginate, induced by
electrostatic repulsion [199]. In comparison, polyelectrolyte complexes, PDADMAC coexist with
ionized COOH, resulting in a diminishing swelling ratio [200]. Alongside the swelling attribute,
investigators often build a framework for the controlled released of therapeutics with other
features, including superporosity and electromechanical sensitivity. Several attempts aimed at the
colon-targeted delivery of rabeprazole sodium by the implementation of biodegradable polymers
for its mucoadhesive properties, generated from crosslinking O-carboxymethyl-chitosan and
carbopol with a Ca2+ ionic cross-linking [201]. CMSP hydrogel displays the
ionic crosslinking with Al3+ for colon-targeted drug delivery. A CMSP hydrogel, filled with 5-
aminosalicylic acid (5-ASA), released small levels of 5-ASA at stomach pH and maintained the
release of drugs at colonic pH. The manufacturing of the polymer from industrial waste further
promised minimization of pollutants as well as the costs of formulation [202]. Glutaraldehyde
effectively controlled the release of Buflomedil hydrochloride through the Locust gum with
poly(vinyl alcohol). This combination appropriately controlled the rate of release to short half-
lives and improved the water solubility of the encapsulated pharmaceutical items [203]. The
psyllium-based polymers are other modified polysaccharides widely used in drug delivery
applications. The maximum effectiveness appeared at the pH 7.4 for the product buffer for
psyllium-poly(vinyl alcohol) filled with rabeprazole sodium. The hydrogels possess
hemocompatibility, which suggests their application in pharmaceutical goods for the treatment of
bloating ulcers [204].
Polysaccharide drug-loaded through self-assembling
Hydrophilic polysaccharide backbones construct the self-assembling frameworks, such as
niosomes and liposomes, when they are introduced to hydrophilic polymers [205-207]. The self-
assembly of hydrophobic polysaccharide formulates from the polymer backbones treated with
hydrophobic sections of hydrophilic polysaccharides containing hydroxy, amino or carboxy
groups that eventually form amphiphilic macromolecules. This solubilizes the hydrophobic drugs
molecules in the self-assembling drug delivery polysaccharides. The factors such as fluctuations
in pH, ionic intensity, and temperature further determine the drug release from these
polysaccharides [208]. Self-assembled nanoparticles in hydrophilic polysaccharide frameworks
such as amylose, guar gums, pectin, chitosan, dextran and rubber beans offer wider applications
in the delivery of hydrophobic drugs at the target site. The polysaccharides offer an ideal platform
for colon-target distribution since it shows high stability in the stomach pH, as compared to the
intestine physiological environment as the colon microbiota induces polysaccharide degradation
and eventually release the therapeutics payload into the colon [209]. Polysaccharide-based NPs
such as chitosan armed with therapies like paclitaxel, ibuprofen, and amphiphilic doxorubicin
(DOX) improve the overall therapeutic effect of the drug. Amino groups on Chitosan participate
in the grafting of hydrophobic groups through acylation with acyl chloride or anhydride acid and
ultimately interconnected with deoxycholic acid. Advanced applications such as plasmid DNA
transfection with deoxycholic groups-acid NPs (160 nm) was reported in COS-1 cells [210].
Dextran, often considered the self-assembled nanosized drug carrier, offers the grafting of several
biomolecular moieties such as bile acids, normal amphiphilic steroids, and lauryl strands. Azido-
modified dextran NPs mixed with mannose showed an improved cellular internalization for the
delivery of therapeutic agents. Addition of acrylic acid to dextran generated pH-sensitive NPs
between 40 and 140 nm diameter [211]. The modified dextran effectively improves the absorption
of DOX, hence proving to be a viable transporter for DOX. Dextrin nanogel filled with DOX
minimizes the toxicity of the drug towards normal human cells by reducing the therapeutics side
effects. Chemical transformation of HA to form NPs in the size range 200-400 nm, comparable to
dextran and chitosan conjugated with 5-β cholinic acid offered highly effective treatment of
inactive CD44 tumors. HA shapes amphiphilic chain copolymers when covalently linked to the
poly(γ-benzyl l-glutamate) component [212]. Not only were these nanoparticulates elevated the
cellular uptake by endocytosis, but they have also increased drug toxicity in the target KB cells
[213]. The usage of starch or cellulose-based drug delivery nanoparticles also improved their
solubility in the organic solvents by the introduction of chemical modifications on the hydroxy
and carboxyl groups. These approaches further improved the drug loading capacity onto these
nanocarriers by conjugating with the functional head groups on the polysaccharide surface [214].
 Table 1. Polyaccharides in drug delivery applications.

PS-based Therapeutic agents & Type of Cell types Model of study Polymer Advantages References
polymer targeting
Dextran COX-2 siRNA/ Passive Breast cancer cell In vitro and in vivo Biocompatible, pH stimuli- [215]
lines (MDA- responsive, down-regulate
MB231) Cyclooxygenase COX-2 genes in
tumor cells
Dextran- folic DOX/Active Breast cancer cell In vitro and in vivo Reducing the side effect of DOX, [216]
acid line (4T1) enhanced tumor growth
inhibition, and prolonged survival
rate
Dextran- Paclitaxel/ Passive Breast cancer cell In vitro and in vivo Enhanced cellular uptake, [216]
Indomethacin line (MCF-7) prolonged pharmacokinetics
(prolonged circulation time and
slower elimination), enhanced
tumor growth inhibition
Dextran- Paclitaxel/ Passive Colorectal cell line In vitro and in vivo Cellular proliferation enhanced [217]
albumin (CT-26) inhibition, inducing apoptosis,
Enhanced drug circulation times
Dextran-folic Resveratrol/ Active Lung cell line In vivo Enhanced cellular apoptosis and [218]
acid (A549) drug intake
Dextran-DOX Doxorubicin/ Passive Lymphoma cell In vitro and in vivo Reduced cytotoxicity (cardiac), [219]
lines enhanced apoptosis, enhanced
intracellular intake leading to
increased DOX concentration that
inhibits tumor growth
Hyaluronic 5-Fluorouracil/ Active Lung cell line In vitro Enhanced cell apoptosis and [220]
acid- Chitosan (A549) & cellular drug accumulation
liver cell line
(HepG2)
Hyaluronic Paclitaxel & curcumin /Active Breast cancer cell In vitro and in vivo Prolonged pharmacokinetics, [221]
acid- Poly- line (MCF-7) Enhanced cellular accumulation
lactic-co-
glycolic acid;
Hyaluronic Paclitaxel/Active Breast cancer cell In vitro Decreased the IC50 of paclitaxel [73]
acid- Poly- line significantly
lactic-co- (MDA-MB-231)
glycolic acid;
Hyaluronic Naringenin/Active Lung cancer cell In vitro and in vivo Enhanced cell apoptosis, [222]
acid- Poly-ε- line (A549) increased drug intake resulting in
caprolactone- inhibiting cancer growth
Chitosan
 Hyaluronic Paclitaxel/Active Breast cancer cell In vitro and in vivo Enhanced cancer growth [223]
acid-Silica line (MCF-7) suppression, increased intake and
drug accumulation
Hyaluronic Doxorubicin & Gemcitabine Breast cancer cell In vitro and in vivo Dual modality drug delivery [224]
acid /Active lines system, enhanced inhibition to
(MDA-MB-231 cancer growth
& 4T1)
Hyaluronic Doxorubicin & Cisplatin /Active Breast cancer cell In vitro and in vivo Tumor growth inhibitor at low [225]
acid- lines drug concentrations
Polyamidoamin (MDA-MB231
e & MCF-7)
Hyaluronic TWIST- siRNAs (Basic helix- Ovarian cancer cell In vitro and in vivo Reduced cancer growth and cell [226]
acid-Silica- loop-helix transcription factors)/ line survival through selective
polyethyleneim Active (Ovcar-8) targeting
ine
Hyaluronic 5-Fluorouracil /Active Colon cancer cell In vitro and in vivo Tumor repression, high [227]
acid-Silica line (HT29) cytotoxicity and high
accumulation in the tumor
through selective targeting
Chitosan- N- DOX/Passive Breast cancer cell In vitro Enhanced cytotoxicity and [228]
acetyl histidine lines MCF-7 cellular uptake
and arginine
 Chitosan- DOX & IL-2/Active Lung cancer cell In vitro and in vivo Increase IgG expression levels, [229]
Trimethyl and line (A549), Increased cytotoxic T
folate Liver cell line lymphocytes
(SMMC-7721)
and hepatoma cell
line
(H22)
Chitosan Suramin and Breast cancer cell In vitro and in vivo Inhibit Breast and lung metastasis [230]
DOX/ Passive line
(MDA-MB231)
Chitosan- DOX and IL17RB Breast cancer cell In vitro Decrease tumor cellular viability, [231]
Carboxymethyl siRNA/ Passive line inhibits growth, tumor cells
dextran (MDA-MB361) migration, and proliferation
Chitosan- Curcumin/Passive Colon cancer cell In vitro Enhanced cellular uptake, [232]
Hyaluronic line (HT29) reduced cellular proliferation, and
acid- high toxicity
sulfobutyl-
ether-β-
cyclodextrin
Alginate DOX/Passive Melanoma cell line In vitro and in vivo Inhibit tumor growth, higher [233]
(B16) cellular uptake, high cytotoxicity
Alginate Gold NPs (AuNPs) & cisplatin/ Colon cancer cell In vitro and in vivo Tumor growth high inhibition, [234]
Passive line (CT26) enhanced survival
Alginate Paclitaxel/Passive Different breast In vitro and in vivo Promote cell cycle arrest, induce [235]
cancer cell lines apoptosis and reduce the
bioavailability
Alginate- DOX/Active Breast cancer cell In vitro Inhibit tumor progression and [236]
chitosan line (MCF-7) cellular growth
Pullulan Floate & Cervical (Hela) In vitro and in vivo Tumor growth inhibition [237]
Polyethylenimine/Active and liver
(HepG2)
Pullulan- Paclitaxel/Active Liver cancer cell In vitro and in vivo Lower cytotoxicity due to [238]
Folate line selective targeting and prolonged
(SMMC-7721) release
Therefore, the polysaccharide offer a fascinating choice as polymeric material in drug delivery
due to biodegradability and biocompatibility. The application of polysaccharide in drug
delivery is growing very fast as it provides a safe, nontoxic and tunable alternates of synthetic
polymers for the same purpose. The diverse chemical structures, functional groups and
physicochemical properties are making polysaccharides a suitable candidate in drug delivery
[239, 240].
Polysaccharide based controlled release and targeted formulations
Unlike the synthetic hydrophilic polymers, polysaccharide possess a variety of hydrophilic
functional groups on its structure like –OH, -COOH, and –NH2 group which are responsible
for water absorption and further swelling of polysaccharide. These groups grant a variety of
functional capability to the polysaccharide-based systems such as bioadhesion and control
release property. Controlled release property of polysaccharide-based drug delivery systems
has been explored extensively for achieving a prolonged delivery of variety of therapeutics
such as chemotherapeutics, proteins, peptides, nucleic acid and many more [1]. The control
release of therapeutics from the swelled polysaccharide depends on the porosity or degree of
swelling, further regulated by certain parameters like pH, temperature, ionic strength and
electric fields [241]. Several polysaccharides present controlled release and target specific
delivery applications.
1. Chitosan: It is a linear polysaccharide obtained from the exoskeleton of arthropods such as
crabs, lobster, and shrimp and cell walls of fungi. It is available in variety of molecular weight
and degree of acetylation, which control its physical and biological property. Hydroxy and
amino groups on the chitosan are involved in making intra- and intermolecular hydrogen bonds.
The pH dependent protonation of amino group leads to swelling of the Chitosan to form three-
dimension structure gel at pH lower than the pKa [242]. Various chitosan salts such as chitosan
palmitate and chitosan laurate exhibit different degrees of swelling, and thus drug release from
the variety of dosage form. The presence of primary amines in chitosan is responsible for its
biological activity such as antimicrobial, anticancer. Chitosan nanoparticles showed greater
antimicrobial activity against Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas
aeruginosa, and Escherichia coli compared to parent chitosan and chitin [243]. Chitosan-based
controlled release and targeted formulations developed so far are compiled in Table 2.
2. Alginate: It is an extensively studied linear polysaccharide derived from brown seaweed
(Macrocystis pyrifera, Laminaria hyperborean) and from some certain bacteria belonging to
the family Pseudomonas and Azotobacter. Similar to chitosan, aginate also form a thick gel at
low pH, which served as a barrier for controlled release of therapeutics. Additionally, alginate
also form thick gel with certain polyvalent cations (Ca2+ and Na+) due to crosslinking of
carboxylic groups of polysaccharide structure. Due to the bioadhesion property of alginate, it
offers targeted drug delivery applications. So far, this polysaccharide has been explored for
variety of formulations including matrix tablet [244], microspheres [245], pellets [246] and
nanoparticles for targeted and functionalized delivery [247] (Table 2). The combination of S-
nitroso-mercaptosuccinate (a nitric oxide donor) and green tea synthesized silver nanoparticles
incorporated into alginate hydrogel showed synergistic antimicrobial activity against
Staphylococcus aureus, Escherichia coli and Streptococcus mutants compared to individual
compounds [248].
3. Pectin: Pectin is a complex polysaccharide present almost one third of the dry cell wall
material of most of the plants. These are higher molecular weight (50,000 and 150, 000 Da)
polysaccharides consist α-(1-4) linked esterified D-galacturonic moiety. Various
physicochemical parameters of pectin like solubility, viscosity and gelling properties depends
upon the degree of methyl esterification of D-galacturonic moiety. Depending upon the degree
of esterification two types of pectin are commercially available; highmethoxyl pectins (degree
of esterification > 50) and low methoxyl pectins (degree of esterification < 50) [249]. Various
plant pectins reportedly exhibit applications as controlled release excipients in tablet, hydrogels
and pellets. Additionally, plant pectins offer applications in colon targeted drug delivery due
to their biodegradation potential by colonic microflora [250]. The pectin polysaccharide from
Ulmus pumila L. (PPU) possess potent anti-inflammatory activity. It was observed that the
selenized-PPU inhibit lipopolysaccharide (LPS)-stimulated nitric oxide release by targeting the
protein expression of inducible nitric oxide synthase in murine macrophage cell line RAW
264.7 [251].
4. Guar Gum: It is a high molecular weight linear polysaccharide obtained from the seeds of
the plant Cyamopsis tetragonoloba. The polysaccharide consist of linear chain of (1 → 4)-
linked β-D-mannopyranosyl units with (1 → 6)-linked α-D-galactopyranosyl residues as side
chains with the ratio of mannose to galactose units as 2:1. This polysaccharide swells in polar
solvent and thus has been widely explored for various pharmaceutical applications. Addition
of ionic and non-ionic additives (sodium chloride and glycerin) could change the swelling and
erosion property of polysaccharide for offering a variety of applications [14]. This
polysaccharide serves as tablet binder sustain release polymer and viscosity enhancers. This
polysaccharide has become the primary choice as excipient in colon specific oral product as it
remain indigestible in upper GIT and completely degrades by the colonic microflora [252].
Gamal-Eldeen prepared guar gum C-glycosylated derivative (GG) and its sulphated derivative
(SGG) to investigate its anti-cancer and anti-inflammatory potency. It was observed that GG
inhibits cytochrome P450 1A (a carcinogen activator enzyme) and stimulated the carcinogen-
neutralizing enzymes such as glutathione-S-transferases. Furthermore, both GG and SGG were
able to exert anti-inflammatory by reducing the release of nitric oxide and tumour necrosis
factor-alpha in LPS induced RAW264.7. GG and SGG also inhibited the proliferation of human
hepatocellular carcinoma cells (Hep G2), while only SGG was particularly toxic for MCF-7
[253]. Table 2 presents the selected applications of guar gum as pharmaceutical excipients.
5. Starch: Starch is a naturally available polysaccharide obtained from plants. Its characteristic
properties such as biotolerance and non-immunogenicity for human use, and easy availability
make it a commonly used polymers/pharmaceutical excipient [254, 255]. In comparison to
other polymers such as gum and cellulose, starch does not need to undergo excessive
purification, as they are relatively pure. Structurally, starch has two different glucan chains a.
amylose (linear polymer) and b. amylopectin (branched polymer) representing 98-99% of the
dry weight. In the production of capsules and tablets, starch is widely utilized as a lubricant,
diluent, binder and disintegrant whereas it is also commonly employed for variety of
specialized drug delivery applications, for example delivery of specialized drug and targeting
specific parts of human body [256]. The microsphere of oregano essential oil prepared by
starch-based material utilizing supercritical fluid technology showed superior antioxidant
capacity (in terms of oxygen radical absorbing capacity) and stability. Starch-based drug carrier
systems present high efficacy in the oral delivery of insoluble drugs [257]. Luo et al. (2020)
encapsulated curcumin into starch microparticles and the formulation showed enhanced
stability against photodegradation and oxidative modification. Furthermore, the size of
curcumin starch microparticles was possible to control accurately from 0.3-2µm by altering the
rate of debranching reaction that caused alteration of release characteristic of curcumin. These
observations suggested the management of the release site by modifying the crystallinity or
size of microparticles [258]. Alp et al. 2019, formulated starch nanoparticles for the delivery
of epigenetic drugs CG-1521 for breast cancer that inhibits histone deacetylase. The
nanoparticles formulation showed decrease release rate of CG-1521 allowing remarkable
cytotoxicity against MCF-7 breast cancer cell as compared to free CG-1521 [259].
Table 2: Different polysaccharides explored for the sustained release of pharmaceuticals

Polysaccharide Formulation Drug Remark Ref.

Chitosan Oral Tablet Sodium valproate Extended release behavior of embedded drug upto 24 h [260]

Hydrogel Caffeine, Ascorbic acid, Extended drug release upto 24 h [261]

and 5-fluorouracil

Bioadhesive vaginal Fluconazole Delayed release with T80 17.4 h [262]

tablet
Dry powder inhaler Rifampicin and Sustained release at pulmonary region, upto 12 h for [263]
Rifabutin
rifampicin and up to 96 h for rifabutin
Alginate Matrix Tablet Metronidazole Effect of particle size of drug, additive used, and pH of [244]
medium was evaluated on drug release
Microspheres Blue dextran Extended drug release upto 24 h [245]

Pellets Theophylline Incorporation of Ca salt prolong the drug release [246]

Nanoparticles Cisplatin Folate conjugation provide selectively taken up by HNE-1 [247]

cells and Hep-2 cells
Pectin Colon specific Methotrexate Microparticles were prepared by ion gelation method [250]
microparticles
 Nanoparticles Diclofenac sodium Nanoparticles were able to release the drug for prolonged [264]
period of time
Pectin coated Vitamin C Significant improvement in permeation [265]
liposome
Guar gum Colon Tablet Metronidazole More availability of drug at colon [252]

Folic acid Methotrexate Enhanced uptake of delivery systems by colorectal cancer [266]
conjugated cells
nanoparticles
Nanoaggregates Isoniazid and Formulations shows enhanced local action due to sustained [267]
Rifampicin
release
Hydrogel Rifampicin Enhance mucoadhesion thus better efficacy [268]

Starch Microspheres Oregano essential oil High antioxidant activity values and stability [257]

Microparticles Curcumin Enhance stability against photodegradation and chemical [258]

oxidation

Nanoparticles CG-1521 (histone Decrease release rate of CG-1521 allowing remarkable [259]
deacetylase inhibitor)
cytotoxicity against MCF-7 breast cancer
Polysaccharides as emulsion stabilizers
The amphiphilic nature of chemically modified polysaccharides causes their adsorption at the
interface of oil and aqueous solvents that results in the stabilization of the emulsion [269]. This
property of polysaccharides proved highly beneficial for the delivery of lipophilic or non-polar
therapeutics at their target site [270]. As such, the native cellulose does not offer emulsion
stabilization due to its non-solubility in water. The chemically modified cellulose not only
improves its aqueous solubility but also affords the stabilization of the emulsion [271]. The
large size of polysaccharides slows down their adsorption process compared to the small sized
surface-active agents. Mainly, the polysaccharide-based emulsifiers mainly base on pectins,
gum arabic, galactomannans, and cellulose. Cellulose and starch promote the emulsion
stabilization only after their chemical modification however; the polysaccharides such as gum
arabic and pectins endowed with covalently linked glycoproteins possess intrinsic ability for
the stabilization of the emulsion. In addition, the polysaccharides such as xanthan gum,
carrageenan, alginates, hyaluronan, chitosan, and alginates that display trivial interfacial
activity offer the eulsion stabilization via thickening, gelling, and structuring [272]. The
structural relationship between chitin-based nanomaterials to that of cellulose results in a
similar amphiphilic behavior for potential applications as stabilizers of oil-in-water Pickering
emulsion. Starch microgranules demonstrate similar applications however; the nanocrystals
and nanospheres of starch exhibit a limited stabilization of the emulsion [273]. Yan et al. 2019
reported the stabilization of Pickering emulsions droplets by nanocrystals of bacterial cellulose
for hydrophobic drug delivery of Alfacalcidol. The irreversible adsorption of bacterial cellulose
nanocrystals at the oil-water interface of Pickering emulsions prevented the coalescence of the
droplets. The emulsion showed Ostwald ripening in the alginate solution. The interfacial
assembly of the amphiphilic bacterial cellulose nanocrystals and the hydrogel shells of the
alginate beads generated by the external gelation led to the achievement of efficient loading
and a controlled release of Alfacalcidol. The release mechanism of Alfacalcidol from the
composite beads followed non-Fickian transport. The alginate composite beads demonstrated
minimal toxicity that further proved beneficial for drug delivery applications. Koshani et al.
2021 presented the lipophilic drug delivery applications via natural emulgel obtained from
dialdehyde cellulose crosslinked with chitosan. The delivery of the lipophilic compound β-
carotene occurred using an embedded oil-in-water emulsion. The lipophilic β-carotene loaded
in the oil-phase showed 20% release in stomach after passing safely through the oral cavity.
Furthermore, 50% of β-carotene released in the intestines after 4h in the presence of emulgel
thereby indicating its application as oral delivery vehicle [274].
Clinical trials on Polysaccharide based drug delivery systems
Riedl et al. (1993) performed phase I clinical trials on the dextran-conjugated doxorubicin on
13 patients at a starting dose of 40 mg/m2 that led to the development of WHO grade IV
thrombocytopenia in 2/2 patients. Whereas, the WHO grade IV hepatotoxicity, and WHO grade
III cardiotoxicity appeared in patients with preexisting heart ailments. Lowering of the dose to
20 mg/m2 further decreased the existence of thrombocytopenia. However, the hepatotoxicity
persisted. Further reducing the dose to 12.5 mg/m2 caused marked reduction in the malignancy
fibrous histiocytoma for up to 4 months [275]. Soepenberg et al. (2005) performed phase I
clinical trials on DE-310, a camptothecin analog, and a carboxymethyldextran polyalcohol
carrier, in the patients with advanced solid tumors. The DE-301 drug delivery system
reportedly released DX-8951 drug slowly, while maintaining a sustained release. This
prolonged the drug exposure at its deliberated tumor site. Some patients showed partial-to-
complete remission of metastatic adenocarcinoma at dose 7.5 mg/ m2 [276]. Kim et al. (2006)
conducted phase II clinical trials on holmium 166/ chitosan complex for the effective treatment
of hepatocellular carcinoma. The percutaneous administration of the nanosystem caused a
complete tumor necrosis in 31/40 patients after 2 months period. However, a long-term follow-
up period indicated recurring of tumor in 28 patients. The polysaccharide based drug delivery
system proved beneficial for the treatment of small hepatocellular carcinoma by performing
local ablative procedure [277]. Pinnix et al. (2012) performed single-blind randomized phase
III clinical trials on topical hyaluronic acid after adjuvant radiotherapy for breast cancer. The
topical hyaluronic based gel did not proved effective for the treatment of grade 2 dermatitis
following radiotherapy [278]. Pritchard et al. (2016) reported phase II clinical trials on
oligosaccharide polymer therapy for modification of mucus barrier of COPD. The binding of
the oligosaccharide caused alteration in the surface charge, porosity, and 3-D mucin networks
in sputum of patients with cystic fibrosis, and its inhalation in patients caused effective
deposition in lungs and altered the viscoelasticity of the cystic fibrosis sputum [279].
Conclusion and Future perspectives
The polysaccharide based drug-delivery vehicles traversed a long journey for the controlled
release of pharmaceuticals at the target site with minimized ensuing side effects caused by the
customary delivery vectors. The biodegradability and trivial immunogenicity of the
polysaccharide-based drug delivery vehicles makes them the material of the future. The
controlled release profile offers improved drug pharmacokinetics thereby leading to
ameliorated local action, and effectivity. As such, the polysaccharides present the first-in-class
drug delivery system ‘Novochizol’ for the delivery of COVID-19 drugs. The system comprises
of biodegradable and biocompatible chitosan nanoparticles that strongly adhere to the lung
epithelium and offers a sustained drug-release. Similarly, the recent discovery of helical V-
amylose as advanced drug delivery system further validated the precedence of polysaccharides
as drug delivery vehicles. The helical morphology of V-amylose offers drug encapsulation in
the helix groves while interacting with the functional head groups. This system proved highly
advantageous for the delivery of indomethacin, diclofenac, and aspirin with enhanced gastric
tolerance. The conjugation of polysaccharides with metal nanoparticles with unique
physicochemical profile in the form of optical, electronic, magnetic, and surface properties
provide nanoprobes that present a sturdy candidature in bioimaging of the effected site, while
delivery the cargo pharmaceutical at the same time. The development of multicompartmental
microspheres based on polysaccharides revolutionized bioengineering and multi-drug delivery
with high precision. The coaxial electrospun fiber membranes based on polysaccharides
transformed the plant grafting techniques and effectively managed the plant tissue injury due
to their high mechanical and tensile strength. The biological phenomenon such as wood
degradation by brown-rot fungi led to the development of bioinspired, core shell cellulose
microparticles for the light-triggered release of anticancer drugs. Furthermore, the stabilization
of Pickering emulsions by chemically modified polysaccharides play a significant role in the
lipophilic drug delivery applications, and targeted delivery of various pharmaceuticals and
bioactive ingredients.
Despite several benefits, the polysaccharide-based formulations suffer limitations such as
susceptibility towards microbial contamination, uncontrolled hydration rate, and reduced
viscosity during storage. To overcome these limitations, it mandates the modification of natural
polysaccharides via cross-linking, grafting, and blending with natural and synthetic polymers
to improve their physicochemical profile. Similarly, the limited knowledge about the
mechanism of drug release by polysaccharides, and permeation enhancement decelerates the
progressive developments in polysaccharide-based drug delivery systems.

Conflict of Interest: The authors have no conflict of interest

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