International Journal of

Molecular Sciences

Review
Versatile Types of Polysaccharide-Based Drug
Delivery Systems: From Strategic Design to
Cancer Therapy
Yanzhen Sun 1,† , Xiaodong Jing 1,† , Xiaoli Ma 2 , Yinglong Feng 1 and Hao Hu 1, *
1 Institute of Biomedical Materials and Engineering, College of Materials Science and Engineering, Qingdao
University, Qingdao 266071, China; [email protected] (Y.S.); [email protected] (X.J.);
[email protected] (Y.F.)
2 Qingdao Institute of Measurement Technology, Qingdao 266000, China; [email protected]
* Correspondence: [email protected]
† These authors contributed equally to the paper.




Received: 19 November 2020; Accepted: 30 November 2020; Published: 1 December 2020


Abstract: Chemotherapy is still the most direct and effective means of cancer therapy nowadays.
The proposal of drug delivery systems (DDSs) has effectively improved many shortcomings of
traditional chemotherapy drugs. The technical support of DDSs lies in their excellent material
properties. Polysaccharides include a series of natural polymers, such as chitosan, hyaluronic acid,
and alginic acid. These polysaccharides have good biocompatibility and degradability, and they are
easily chemical modified. Therefore, polysaccharides are ideal candidate materials to construct DDSs,
and their clinical application prospects have been favored by researchers. On the basis of versatile
types of polysaccharides, this review elaborates their applications from strategic design to cancer
therapy. The construction and modification methods of polysaccharide-based DDSs are specifically
explained, and the latest research progress of polysaccharide-based DDSs in cancer therapy are also
summarized. The purpose of this review is to provide a reference for the design and preparation of
polysaccharide-based DDSs with excellent performance.

Keywords: polysaccharide; drug delivery system (DDS); chemotherapy; cancer therapy

1. Introduction
As a systemic treatment method, chemotherapy is still the most commonly used method for
cancer therapy. Chemical drugs can be used in chemotherapy to block the proliferation, infiltration,
and metastasis of tumor cells, thereby killing cancer cells [1]. However, there are still several challenges
to make chemotherapy drugs work smoothly in tumor tissues and cells: (i) short blood circulation
time and poor water solubility make the bioavailability of small molecule drugs low; (ii) long-term
medication makes tumor cells resistant to chemotherapy drugs; (iii) chemotherapy drug molecules
cannot specifically reach the tumor site and penetrate normal tissues indistinguishably, leading to
nausea, vomiting, diarrhea, constipation, alopecia, and decreased liver function, which aggravates the
suffering of patients. Fortunately, with the rapid development of nanotechnology, new nanomedicine
technologies that are applied to the field of cancer treatment have gradually emerged. By embedding,
adsorbing, or covalently coupling traditional chemotherapeutic drug molecules onto/into a nano-sized
carrier, researchers have proposed drug delivery systems (DDSs) [2]. Through various functional
modifications to the carrier, this system has the advantages that traditional drug molecules cannot
match. Compared with traditional drug molecules, DDSs possess better water solubility and stability,
higher specific delivery in vivo, lower toxic side effects, and higher anti-tumor effect [3]. At present,

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Int. J. Mol. Sci. 2020, 21, 9159 2 of 21

a wide variety of DDSs have been developed and applied, such as proteins, polysaccharides, synthetic
polymers, and organo–inorganic hybrids [4–7]. Among them, the polysaccharide is a natural polymer
formed by dehydrative condensation of multiple monosaccharide molecules [8]. The polysaccharides
commonly used in the biomedical materials field include hyaluronic acid [9], chitosan [10], dextran [11],
alginate [12], and chondroitin sulfate [13]. These polysaccharides are safe and non-toxic, easily
biodegradable and chemically modified, and have good water solubility and biological activity (such as
anti-tumor, anti-viral, anti-oxidation, and anti-inflammatory effects, as well as prevention of various
cardiovascular diseases). Moreover, large reserves and low production costs make polysaccharide
products easy to produce on a large scale.
Polysaccharides are rich in sources and can be obtained from various natural renewable resources
(ocean and plant). A lot of functional groups such as hydroxyl (-OH), amino (-NH2 ), or carboxyl
(-COOH) hang on the molecular chain of polysaccharide. The presence of these groups makes it easy
for polysaccharides to be chemically modified [14]. By changing the physical and chemical properties of
polysaccharides, structures such as vesicles, micelles, and hydrogels are formed. In recent years, a series
of controllable polymer-grafted polysaccharides are made by living radical polymerization (LRP) and
ring-opening polymerization (ROP) [15,16]. These modified polysaccharides have a great application
prospect in drug delivery, gene delivery, and wound dressing [17–20]. Liposomes, micelles, and
hydrogels modified by polysaccharides have been widely used as excellent anti-tumor DDSs [21–23].
While maintaining the advantages of polysaccharide materials, such DDSs also possess various
advantages of nanoscale systems. Polysaccharides are one of the candidates for constructing hydrogels
and have been extensively studied. Polysaccharide-based hydrogels loaded with drugs or bioactive
molecules are widely used as wound dressings, and many products have been commercialized [24].
In situ injectable polysaccharide-based hydrogel is a good local sustained-release carrier and may be
able to isolate tumors from normal tissues [25,26].
In view of the excellent performance of polysaccharide-based DDSs, this article presents the overall
situation of versatile types of polysaccharide-based DDSs for cancer therapy. The design strategies and
considerations about polysaccharide-based DDSs are discussed, and the advanced research progress in
the field of tumor therapy are summarized. Finally, we outline the research prospects and application
value of polysaccharide-based DDSs.

2. Design Strategies
Polysaccharides are composed of monosaccharides, including D-glucose, D-galactose, D-fructose,
D-mannose, D-xylose, L-galactose, and L-arabinose, which are combined by glycosidic bonds [27].
Polysaccharides are mainly derived from various natural products, such as alginic acid from algae,
pectin and guar gum from plants, dextran and xanthan gum from microorganisms, and chitosan
and chondroitin from animals [28]. Polysaccharide materials derived from nature not only have
inherent environmental friendliness, but also adapt well to cell physiology. Drug carriers have been
widely studied as auxiliary materials for the delivery of chemotherapeutics. Inorganic nanoparticles,
liposomes, micelles, and hydrogels are currently the most commonly used drug systems [29].
By modifying polysaccharide molecules, derivatives with different functional groups and conjugates
can be obtained, which is conducive to further synthesis of drug carriers. In order to reduce the
side effects during chemotherapy and prevent the excessive use of drugs, it is of great significance
to study how to combine polysaccharides with drugs to construct DDS. For polysaccharide-based
drug delivery systems, the design strategies can be broadly divided into three types: (i) coupling
polysaccharides and drugs through cleavable chemical bonds to construct polysaccharide–drug
conjugate carriers [30]; (ii) self-assembling to form polysaccharide-based drug-loaded particles [31];
(iii) encapsulating drug molecules in polysaccharide-based hydrogels [32]. The common design
strategies of polysaccharide-based DDS are shown in Figure 1.
Int. J. Mol. Sci. 2020, 21, 9159 3 of 21

Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 20

Figure1.1.The
Figure Thedesign
designstrategies
strategiesof
ofpolysaccharide-based
polysaccharide-baseddrug
drugdelivery
deliverysystems
systems(DDSs).
(DDSs).

2.1.
2.1. Constructing
ConstructingPolysaccharide–Drug
Polysaccharide–DrugConjugates
Conjugates
Natural
Natural or orsynthetic
syntheticwater-soluble
water-soluble polymers
polymers are are usually
usually applied
applied toto drug
drugcoupling
coupling totodevelop
develop
various
variousprodrugs
prodrugs[33].[33]. The
The composition
composition of of monosaccharides
monosaccharides isis diversified,
diversified, with
with neutral
neutralhydroxyl
hydroxyl
groups,
groups,negatively
negativelycharged
chargedcarboxylic
carboxylic acid/sulfate
acid/sulfate groups,
groups, oror positively
positively charged
charged amine
amine groups
groups [34].
[34].
Connections
Connections between monosaccharide units are variable (such as linear chain structure andbranched
between monosaccharide units are variable (such as linear chain structure and branched
chain
chain structure),
structure), and
and there
therearearealso
alsogreat
greatchanges
changesininmolecular
molecularweight.
weight. These
These complex
complex chemical
chemical
connections
connections provide the basis for the huge chemical diversity of polysaccharides. Hydroxyl
provide the basis for the huge chemical diversity of polysaccharides. Hydroxyl (-OH),
(-OH),
carboxyl
carboxyl(-COOH),
(-COOH),and andamino
amino(-NH
(-NH2 )2on
) onthe
thepolysaccharide
polysaccharide molecules
molecules areare
thethe
main active
main sites
active used
sites to
used
construct polysaccharide-based
to construct polysaccharide-based DDS. DDS.
Polysaccharides
Polysaccharides can form
canpolysaccharide–drug carriers through
form polysaccharide–drug carriers
non-covalent interactions or covalent linkage reactions with drug
through non-covalent interactions or covalent linkage reactions with drug molecules. molecules. Common construction
Common
methods include
construction (i) esterification
methods include of(i)hydroxyl groups with
esterification acylating agents,
of hydroxyl groups etherification of hydroxyl
with acylating agents,
groups with alkylation agents, oxidation of primary alcohols to carboxyl groups,
etherification of hydroxyl groups with alkylation agents, oxidation of primary alcohols to carboxyl and oxidation of
vicinal secondary hydroxyl groups to aldehydes; (ii) ester bonds consisting of hydroxyl
groups, and oxidation of vicinal secondary hydroxyl groups to aldehydes; (ii) ester bonds consisting groups linked
to
ofcarboxyl
hydroxyl groups,
groupsamide
linked bonds consisting
to carboxyl of carboxyl
groups, amidegroups
bonds linked to amino
consisting groups,groups
of carboxyl and hydrazone
linked to
bond formed by reaction of -COOH and
amino groups, and hydrazone bond formed by -NHNH ; (iii) interaction between amino
2 reaction of -COOH and -NHNH2; (iii) groups andinteraction
hydroxyl
or carboxyl
between groups
amino [35]. and hydroxyl or carboxyl groups [35].
groups

2.2. Self-Assembling Polysaccharide-Based DDS

2.2. Self-Assembling Polysaccharide-Based DDS
2.2.1. Cross-Linking between Polymeric Electrolyte and Ion
2.2.1. Cross-Linking between Polymeric Electrolyte and Ion
Charged polysaccharides can be cross-linked through interaction with oppositely charged polymers
Charged polysaccharides can be cross-linked through interaction with oppositely charged
or simple ions. The polymeric electrolyte self-assembly system of polysaccharides is mainly based on
polymers or simple ions. The polymeric electrolyte self-assembly system of polysaccharides is mainly
the mutual attraction of positively charged chitosan (or chitosan oligomers) and negatively charged
based on the mutual attraction of positively charged chitosan (or chitosan oligomers) and negatively
polyanionic polysaccharides (including carboxymethyl cellulose [36], carboxymethyl glucomannan [37],
charged polyanionic polysaccharides (including carboxymethyl cellulose [36], carboxymethyl
carboxymethyl chitosan (CMC), dextran sulfate [38], alginate [39], heparin [40], octenyl succinic anhydride
glucomannan [37], carboxymethyl chitosan (CMC), dextran sulfate [38], alginate [39], heparin [40],
octenyl succinic anhydride starch (OSA starch) [41], carboxymethyl starch, and hyaluronic acid [42]).
The hydrogel constructed by ionic crosslinking can be adapted to pH-controlled drug release by
adjusting swelling and dissolution [43]. For example, alginate can chelate polyvalent metal ions (such
as calcium ions) to form nano-scale gels. These gels have been widely used as sustained DDS due to
Int. J. Mol. Sci. 2020, 21, 9159 4 of 21

starch (OSA starch) [41], carboxymethyl starch, and hyaluronic acid [42]). The hydrogel constructed
by ionic crosslinking can be adapted to pH-controlled drug release by adjusting swelling and
dissolution [43]. For example, alginate can chelate polyvalent metal ions (such as calcium ions) to
form nano-scale gels. These gels have been widely used as sustained DDS due to their excellent
biocompatibility and non-immunogenicity [44]. Carboxymethylated chitosan can be transformed into
nanoparticles by interacting with calcium ions. The particle size distribution can be controlled by
adjusting the addition parameters of calcium ions [45].

2.2.2. Self-Assembly of Hydrophobic Polysaccharides

Micelle is a kind of widely used nanocarrier. The polymers forming micelles have hydrophilic
and hydrophobic moieties, which can self-assemble into micelles in aqueous solution to achieve
solubilization and encapsulation of drugs. The hydrophobic core facilitates the micelles to carry
drugs with different properties; the hydrophilic shell helps drug-loaded micelles to escape the
phagocytosis of mononuclear phagocytes. Polysaccharide molecules themselves are not amphiphilic
and cannot form polymer micelles through self-assembly. By introducing hydrophobic molecules into
the hydrophilic polysaccharide backbones, the resulting amphiphilic polysaccharide molecules have
the ability to self-assemble into nanoscale micelles in aqueous solution [46]. Polymer liposome is a kind
of spherical molecular aggregate formed by self-assembly of amphiphilic polymers. It has a bilayer
membrane structure similar to human cell membranes. The preparation of polysaccharide-composed
liposomes is similar to that of polysaccharide-based micelles, and the hydrophobic modification of
polysaccharide molecules is also required [47]. Hydrophobic molecules such as cholesterol, steroid acid,
deoxycholic acid, and hydrophobic polymers are commonly used to modify polysaccharide molecules.
They allow polysaccharide-based amphiphilic polymers to self-assemble into micelles or liposomes
by minimizing interface free energy [48]. Hydroxyl, amino, and carboxyl groups on the hydrophilic
polysaccharide skeleton are commonly used sites for hydrophobic grafting. Liposomes have the ability
to simultaneously carry hydrophilic drugs and hydrophobic drugs. The unique bilayer structure of
liposomes allows both hydrophobic and hydrophilic microdomains to exist. The water-soluble drugs are
encapsulated in the hydrophilic cavity of the liposome, while the hydrophobic drugs are located in the
hydrophobic microphase between the two phospholipid bilayers of the liposome. The controlled release
of drugs can be realized according to the change of microenvironment (temperature, pH, etc.) [49].

2.3. Preparation of Drug-Loaded Polysaccharide-Based Hydrogels

Hydrogel is a kind of polymer with three-dimensional network structure [50]. With high water
content and hydrophilicity [51], the hydrogel can quickly inhale and store water far exceeding
its own volume [52]. Polysaccharides are good candidates for the preparation of drug-loaded
polysaccharide-based hydrogels. Nanoscale gel particles also have great advantages in the controlled
release of anti-tumor drugs [53]. Drug molecules can be encapsulated in the matrix of the gel through
non-covalent interactions (such as salt bond, hydrogen bonds, and hydrophobic interaction), and the
drug can be released from the gel through the expansion of the grid [54]. Some prodrug molecules
can also self-assemble into hydrogels to realize self-delivery and sustained release [55]. For instance,
after encapsulating the chemotherapy drug doxorubicin (DOX), the hydrogel was injected into tumor
tissues, which could isolate tumor cells and achieve long-term drug release in local tumor [56].
Int. J. Mol. Sci. 2020, 21, 9159 5 of 21

3. Functionalization of Polysaccharide Molecules

In order for researchers to achieve targeted drug delivery and precise control of drug release
behavior in tumor lesion tissues, it is of great significance to construct functional DDS that respond
to the tumor microenvironment in order to achieve active targeting or self-degradation functions.
Considering that polysaccharide-based carriers can be non-specifically recognized and adsorbed by
plasma proteins, allowing selective uptake of the carrier by the reticuloendothelial system results in a
decrease in the bioavailability of the carrier and limiting the therapeutic effect of the drug. Therefore,
it is necessary to modify the structure of the polysaccharide molecule, constructing the carrier so that it
achieves specific recognition and adhesion to tumor tissue. The introduction of different functional
groups to modify polysaccharides (such as in situ disulfide bond modification) during the construction
of polysaccharide-based carriers can make these carriers environmentally responsive. By responding to
the stimulation of the tumor microenvironment (pH, glutathione (GSH), etc.), the biodegradation rate
of the carrier is changed, and then the drug release rate is adjusted. The commonly used functionalized
types of polysaccharide molecules are summarized in Table 1.

Table 1. The commonly used functionalized types of polysaccharide molecules.

Functional Types Modification Methods Features References

Aldehyde modification to
Modification of functional pH-responsive capability [21]
generate Schiff base
molecules
Targeting ligand modification Tumor cell targeting ability [57,58]
Molecular chain grafting Grafting hydrophobic segment Amphiphilicity [59–61]
Response to the reducing
Disulfide bond [62,63]
Introduction of cleavable microenvironment
bonds Respond to the weak acid
pH-sensitive groups [64]
microenvironment

3.1. Modification of Functional Molecules on Polysaccharide Molecules

By modifying tumor cell-specific recognition ligands (such as antibodies, polypeptides, small
molecules, and aptamers) on polysaccharide molecules, researchers endow polysaccharide-based
DDSs with active tumor targeting, thereby improving the choice of anti-tumor drugs in vivo and
enhancing the anti-tumor effect. For example, after being modified with folic acid molecules (FA),
the targeting ability of chitosan-composed micelle was improved [57]. When chitosan is attached with
DOX, an amphiphilic polymer is formed, which can form micelles in solution. Then, the constructed
DDS has nuclear targeting function after being modified with FA. In vivo experiments proved that
the chitosan-composed micelle could be an ideal DDS for tumor therapy [58]. If the polysaccharide
molecular structure contains a large number of ortho hydroxyl groups, periodate can be used to oxidize
the ortho hydroxyl groups to aldehyde groups. Aldehyde groups can be further derivatized and
convert into reversible covalent bonds such as imines, oximes, acetals, and hydrazones [65]. Aldehydes
and ketone groups can undergo condensation reactions with amine compounds to form Schiff base
structures, which can be degraded rapidly in an acid environment. Therefore, aldehyde modification
is a common method to prepare pH-responsive polysaccharide-based DDS [66]. Fan et al. prepared a
covalent and injectable chitosan/chondroitin sulfate hydrogel embedded with chitosan microspheres
for drug delivery and tissue engineering. The chondroitin sulfate was oxidized to oxidized chondroitin
sulfate (OCS) first and then reacted with CMC via Schiff base cross-linking reaction to form hydrogels.
Bovine serum albumin (BSA)-loaded chitosan-based microspheres (CMs) were encapsulated in the
hydrogel as an active component (Figure 2) [21].
modification is a common method to prepare pH-responsive polysaccharide-based DDS [66]. Fan et
al. prepared a covalent and injectable chitosan/chondroitin sulfate hydrogel embedded with chitosan
microspheres for drug delivery and tissue engineering. The chondroitin sulfate was oxidized to
oxidized chondroitin sulfate (OCS) first and then reacted with CMC via Schiff base cross-linking
reaction
Int. J. Mol.to form
Sci. 2020,hydrogels.
21, 9159 Bovine serum albumin (BSA)-loaded chitosan-based microspheres (CMs)
6 of 21
were encapsulated in the hydrogel as an active component (Figure 2) [21].

Figure
Figure2.2.(a)
(a)Chemical
Chemicalstructures
structuresof ofcarboxymethyl
carboxymethylchitosan
chitosan(CMC)
(CMC)andandoxidized
oxidizedchondroitin
chondroitinsulfate
sulfate
(OCS). (b)
(OCS). (b) Reaction
Reaction scheme to show aa preparation
preparationof
ofchitosan-based
chitosan-basedmicrospheres
microspheres(CMs)
(CMs)embedded
embedded in
CMC–OCS
in CMC–OCS composite gelgel
composite scaffold (CMs/gel).
scaffold Modified
(CMs/gel). Modified from [21].
from [21].

3.2. Molecular Chain Grafting

The chemical properties of a polymer can be controlled by grafting side chains. The grafted chains
can be controlled precisely by using the free radical polymerization method. Meanwhile, the branched
chains introduced by covalent bonds have long-term chemical stability [67]. The amphiphilic graft
polymer with high graft density and narrow molecular weight distribution can be obtained by
modifying the hydrophobic polymer chain segment on the polysaccharide molecule. This method
usually requires the use of active groups on the polysaccharide molecular chain to initiate polymerization
of polymer monomers. Commonly used polymerization reactions include ROP and controlled living
polymerization (CRP) [68]. For example, hydrophobic polymers are grafted onto polysaccharides
by initiating the polymerization of cyclic monomers using hydroxyl groups in the side chains of
polysaccharides. The resulting amphiphilic polysaccharides can self-assemble to form micelles or
liposomes. Currently, commonly used graft polymers include poly(lactic acid) (PLA), polycaprolactone
(PCL), and polyglycolide acid (PGA) [69]. Hu et al. explored different strategies to synthesize and design
controllable polymer-grafted polysaccharides. Through the utilization of LRP, the functionalization
of polysaccharides was realized flexibly and effectively. The grafted substances introduced include
cationic components for nucleic acid delivery, polyethylene glycol and amphiphilic ions for shielding
effects, and polymers for bioimaging and bioactive drug release. Biodegradable polymer-grafted
polysaccharides were prepared by ROP. A series of poly(amino acid)-grafted polysaccharides (linear,
star-shaped, and comb-shaped copolymers) with advanced structures were proposed [59]. Several
polymer-grafted polysaccharides are shown in Figure 3 [70]. However, direct modification methods
are not easy to control the structure and relative molecular mass of polymer segments. Therefore,
it has also been reported that polymeric hydrophobic segments were first synthesized and then
grafted onto polysaccharide molecules after modification by active groups [60]. Compared with
polysaccharides modified by polymeric hydrophobic chain, the polysaccharide molecules modified
with the hydrophobic chain of small molecule possess more uniform chain length and can more
accurately determine the molecular weight of the grafted polymer. Currently, small molecules
commonly used for grafting polysaccharides are lauric acid [71], palmitic acid [72], and stearic acid [73].
Taking polysaccharide molecule as the skeleton, the reaction between the activated small molecule
chain and the group on the polysaccharide molecule chain can obtain an amphiphilic polysaccharide
with a comb-like structure [61].
molecules modified with the hydrophobic chain of small molecule possess more uniform chain length
and can more accurately determine the molecular weight of the grafted polymer. Currently, small
molecules commonly used for grafting polysaccharides are lauric acid [71], palmitic acid [72], and
stearic acid [73]. Taking polysaccharide molecule as the skeleton, the reaction between the activated
small
Int. J.molecule chain
Mol. Sci. 2020, and the group on the polysaccharide molecule chain can obtain an amphiphilic
21, 9159 7 of 21
polysaccharide with a comb-like structure [61].

Figure
Figure 3. Illustration
3. Illustration of theofpreparation
the preparation processes
processes of graftable
of several several graftable polysaccharides.
polysaccharides. Modified
Modified from [70].
from [70].

3.3. Introduction of Cleavable Bonds

Stimuli-responsive DDSs can respond to special microenvironmental states of tumors (weak acidity,
high reductivity, etc.) with changes in structure, size, or shape to overcome physiological barriers
during drug delivery [74]. These changes are usually caused by changes in the structure of the
polymer. By introducing the stimuli-responsive cleavable bonds into the polysaccharide molecules,
the polysaccharide-based DDS can be endowed with the ability to change its structure in response to a
special environment [75]. Disulfide bonds, which can be rapidly cleaved by GSH, are commonly used to
construct reduction-responsive DDSs. Polysaccharide itself does not contain disulfide bond functional
groups, and thus the key to introducing disulfide bond functional groups into polysaccharide-based
DDSs is to make them exist in the crosslinking agents. Generally, substances with disulfide bonds
(e.g., cysteamine dihydrochloride (CYS)) are selected as cross-linking agents to enable DDS to have
redox response ability. Liu et al. prepared a cellulose hydrogel by mixing cellulose acetoacetate and
CYS in an aqueous solution. As a cross-linking agent, CYS introduced disulfide bond functional
groups into the DDS, enabling the DDS to have redox response ability [62]. However, the types
of such crosslinking agents are limited. Therefore, it is meaningful to prepare crosslinking agents
containing disulfide bonds to introduce the disulfide bonds into the DDS. Yang et al. first prepared
the hydrophilic skeleton by modifying dextran with succinic acid. L-phenylalanine ethyl ester
hydrochloride (L-Phe) and L-cysteine ethyl ester hydrochloride (L-Cys) were used as hydrophobic
groups and crosslinking points. The prepared polymer could self-assemble into micelles and load DOX
hydrochloride. At the same time, the hydrosulphonyl could be oxidized into disulfide bond. Therefore,
this nanoparticle had dual pH/redox response capabilities [63]. The introduction of acid-sensitive
cleavable bonds can make polysaccharide DDSs have a pH-responsive ability. Zhang et al. designed
an acid-activated supramolecular nanoprodrug (DOM@DOX) on the basis of dextran. As shown
in Figure 4, the prodrug molecule was connected to hydrophilic polyethylene glycol through atom
transfer radical polymerization (ATRP), and DOX was bound to the main chain of the copolymer
using hydrazone bonds. Through the self-assembly strategy, the synthesized carrier had the ability to
maintain a stable micellar structure in aqueous solution. DOX was released from micelles by breaking
the hydrazone bonds in a slightly acidic environment [64].
acid-activated supramolecular nanoprodrug (DOM@DOX) on the basis of dextran. As shown in Figure
4, the prodrug molecule was connected to hydrophilic polyethylene glycol through atom transfer
radical polymerization (ATRP), and DOX was bound to the main chain of the copolymer using
hydrazone bonds. Through the self-assembly strategy, the synthesized carrier had the ability to
Int. J. Mol. Sci. 2020, 21, 9159 8 of 21
maintain a stable micellar structure in aqueous solution. DOX was released from micelles by breaking
the hydrazone bonds in a slightly acidic environment [64].

Figure 4. Schematic illustration of the synthetic route of acid-activated supramolecular nanoprodrug

Figure 4. Schematic illustration of the synthetic route of acid-activated supramolecular nanoprodrug
(DOM@DOX) micelles, drug accumulation via the enhanced permeability and retention (EPR) effect,
Int. J. (DOM@DOX)
Mol. Sci. 2020, 21,micelles, drugREVIEW
x FOR PEER accumulation via the enhanced permeability and retention (EPR) effect,
8 of 20
cell internalization process, and pH-responsive drug release mechanism. Taken from [64].
cell internalization process, and pH-responsive drug release mechanism. Taken from [64].
4. Advances of Polysaccharide-Based DDSs
4. Advances of Polysaccharide-Based DDSs
Many polysaccharides and their derivatives have been explored and applied in the research of
Many polysaccharides and their derivatives have been explored and applied in the research of
anti-tumor drug delivery carriers. Hyaluronic acid, chitosan, dextran, alginate, and chondroitin
anti-tumor drug delivery carriers. Hyaluronic acid, chitosan, dextran, alginate, and chondroitin sulfate
sulfate (Figure 5) are commonly used materials for constructing delivery systems. These
(Figure 5) are commonly used materials for constructing delivery systems. These polysaccharides
polysaccharides not only have the excellent properties, but also give the carrier special functions
not only have the excellent properties, but also give the carrier special functions during the carrier
during the carrier construction process, such as tumor target of hyaluronic acid and chondroitin
construction process, such as tumor target of hyaluronic acid and chondroitin sulfate, and bioadhesion of
sulfate, and bioadhesion of chitosan and alginate [76]. The following section focuses on the advances
chitosan and alginate [76]. The following section focuses on the advances of polysaccharide-based DDS.
of polysaccharide-based DDS.

Figure 5.
Figure 5. Structures of representative
representative polysaccharides.
polysaccharides.

4.1. Hyaluronic Acid

4.1. Hyaluronic Acid
Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan that mainly exists in vivo as sodium
Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan that mainly exists in vivo as sodium
hyaluronate, which is formed alternately by D-glucuronic acid and N-acetyl-D-glucosamine [77]. HA is
hyaluronate, which is formed alternately by D-glucuronic acid and N-acetyl-D-glucosamine [77]. HA is
an important component of the extracellular matrix and is related to the movement and proliferation
an important component of the extracellular matrix and is related to the movement and proliferation of
cells [78]. In the field of tumor drug delivery, HA derived from the organism itself has low
immunogenicity. More importantly, it can bind to the upregulated cluster of differentiation 44 (CD44)
receptor in cancer cells and mediate the biological behavior of cells [79]. In a low-pH environment (such
as lysosomes), HA could be degraded [80]. The degradation products can bind to macrophages or
Int. J. Mol. Sci. 2020, 21, 9159 9 of 21

of cells [78]. In the field of tumor drug delivery, HA derived from the organism itself has low
immunogenicity. More importantly, it can bind to the upregulated cluster of differentiation 44 (CD44)
receptor in cancer cells and mediate the biological behavior of cells [79]. In a low-pH environment
(such as lysosomes), HA could be degraded [80]. The degradation products can bind to macrophages
or dendritic cell receptors, thereby activating the body’s innate immunity [81]. HA could be easily
chemically modified by esterification reaction and peptide-coupling reaction, and has been used
for targeted drug delivery of paclitaxel drugs (e.g., paclitaxel (PTX) and DOX) [82,83]. A recently
reported tumor-specific self-degradable nanogel based on HA could be used for efficient delivery
of intravenously administered protein drugs (Figure 6). Using a hyaluronic acid derivative named
synthetic cholesteryl-6-aminohexylcarbamate methacrylated hyaluronic acid (cm-HA) as the matrix,
researchers assembled collaboratively crosslinked nanogels (cNG) by using the hydrophobic interaction
between cholesterol groups for physical crosslinking and radical polymerization of methacrylate groups
for chemical crosslinking. In the weak acid environment of the tumor site, acid-activatable HAase
(aHAase) in cNG was partially released, which degraded HA in the extracellular matrix and promoted
the diffusion of the carrier in the matrix. After endocytosis, aHAase was fully activated by acid
lysosomes, the cNG was degraded by activated aHAase, and then the protein drugs contained in cNG
were released and exerted anti-tumor effects [84]. Li et al. prepared HA-based nanoparticles (HA-NPs)
via ion pairing between positively charged DOX and negatively charged HA. Subsequently, HA-NPs
were encapsulated in liposome carriers to obtain DOX-loaded HA-based liposomes (HA-LPs) with
sustained release effects. The presence of HA made the carrier become tumor-targeting, significantly
increased the blood circulation time of DOX, decreased the accumulation of DOX in normal tissues,
and reduced the toxicity of DOX to vital organs of the body [85].
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 9 of 20

Figure 6. (a) Schematic of self-assembly and tumor-specific self-degradation of the collaboratively

Figure 6. (a) Schematic of self-assembly and tumor-specific self-degradation of the collaboratively
crosslinked crosslinked
crosslinked crosslinked nanogels
nanogels (cNG).
(cNG). (b)
(b) Schematic
Schematic of
of enhanced
enhanced protein
protein delivery
delivery by
by the
the cNG
cNG for
for
cancer therapy. Modified from [84].
cancer therapy. Modified from [84].

4.2.
4.2. Chitosan
Chitosan (CS)
Chitosan (CS) is
is an
an important
important derivative
derivative ofof the
the natural
natural polysaccharide
polysaccharide chitin
chitin[86].
[86]. It
It is
is aa natural
natural
cationicpolysaccharide
cationic polysaccharidecontaining
containing amino,
amino, which
which possess
possess goodgood biocompatibility.
biocompatibility. The presence
The presence of aminoof
amino makes
groups groupschitosan
makeseasy chitosan easy to modified.
to be chemically be chemically modified.
CS-based CS-based
DDSs have DDSs have and
low immunogenicity low
immunogenicity
are endowed withand theare endowed
ability withtothe
to adhere ability
the to adhere
negatively to thecell
charged negatively charged
membrane, which cell
is membrane,
conducive
which
to is conducive[87].
cell endocytosis to cellAlthough
endocytosis
CS [87]. Although
has many CS has many
advantages advantages
in drug delivery, in
itsdrug
water delivery, its
solubility
water
is solubilityTherefore,
insufficient. is insufficient. Therefore,
it is often modified it by
is often modified
hydrophilic by hydrophilic
groups groups (suchand
(such as carboxymethyl as
carboxymethyl
quaternary and quaternary
ammonium salt groups).ammonium
CS can besalt groups).to CS
converted CMC can
by be converted to CMC
carboxymethylation by
under
carboxymethylation under the condition of monochloroacetic acid. Compared with CS, the water
solubility, biocompatibility, antibacterial activity, and biodegradability of CMC are improved. CMC
has great development potential in the field of drug delivery [88]. Chi et al. prepared a series of
norcantharidin (NCTD)-conjugated CMC conjugates (CNC) by using CMC as the skeleton [89]. CNC
was found to have a long blood circulation time in vivo, have low distribution in the kidney and
Int. J. Mol. Sci. 2020, 21, 9159 10 of 21

the condition of monochloroacetic acid. Compared with CS, the water solubility, biocompatibility,
antibacterial activity, and biodegradability of CMC are improved. CMC has great development potential
in the field of drug delivery [88]. Chi et al. prepared a series of norcantharidin (NCTD)-conjugated CMC
conjugates (CNC) by using CMC as the skeleton [89]. CNC was found to have a long blood circulation
time in vivo, have low distribution in the kidney and heart, and could effectively inhibit the proliferation
and migration of cancer cells. Wang et al. constructed a new type of DDS by loading galactosylated
chitosan (GC) onto the graphene oxide (GO). The loading capacity of DOX of this DDS was up to
1.08 mg/mg (drug per polymer). The existence of GC enabled the carrier to remain stable under
physiological conditions while achieving drug release in a low pH environment [90]. CS-based DDSs
can also be optimized in combination with physical methods. For example, by inserting the layered
rectorite (REC) into the amphiphilic CMC chains, the prepared nanocarrier has a compact structure.
The introduction of the REC layer enables the carrier to effectively capture DOX. This chitosan-based
carrier can not only effectively increase the loading capacity of DOX, but also exhibit pH sensitivity to
prevent the burst release of the payloads [91]. The presence of CS can promote the release of genes
into the nucleus for enhancing the transfection efficiency of genes. Chen et al. deposited the modified
redox-sensitive amphiphilic CS and HA layer-by-layer on liposomes to obtain a new type of continuous
stimuli-responsive CS-encapsulated nanodrug delivery system (-HA/HAase/CS/liposome/shRNA
(HCLR)). HCLR had the ability to stably exist in the blood circulation and to target and identify tumor
sites, and was able to achieve the delivery of the silence the inhibitor of apoptosis (IAP) inhibitor
survivin-shRNA gene to the nucleus (Figure 7) [92].
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 10 of 20

Figure 7. Schematic of HCLR nanocarrier fabrication and the in vivo fate in breast tumor targeting
Figure 7. Schematic of HCLR nanocarrier fabrication and the in vivo fate in breast tumor targeting
gene delivery. Taken from [92].
gene delivery. Taken from [92].

4.3. Dextran
Dextran, also known
known as asglucan,
glucan,isisaawater-soluble
water-solublepolysaccharide
polysaccharidecompound
compound similar to to
similar starch. It
starch.
is is
It widely
widelyused
usedininthe
theadjuvant
adjuvanttreatment
treatmentofofdiseases
diseasessuchsuchas
as hemorrhagic
hemorrhagic shockshock andand thrombus.
thrombus.
Dextran has colloidal properties, good hydrophilicity and water water solubility,
solubility, and is inert in organisms.
organisms.
The molecular
The molecularchain
chain of dextran
of dextran is richisinrich in hydroxyl
hydroxyl groups,
groups, which which is convenient
is convenient for chemical for chemical
modification.
modification. These properties provide favorable conditions for the construction
These properties provide favorable conditions for the construction of dextran-based DDSs. Dextran of dextran-based
DDSs.
has Dextran
been used tohas been used
construct to construct
carriers carriers
of hydrogels [93],ofmicelles
hydrogels
[94],[93],
and micelles
core–shell [94], and core–shell
structures [95] for
structures
in [95] for
vivo delivery ofin vivo delivery
siRNA and proteinof siRNA
drugs.and protein
Such drugs.
carriers can Such carriers
achieve can achieve
controlled releasecontrolled
of drugs
release
and of drugs
avoid and avoid the
the inactivation inactivation
of drugs of drugs
in the body dueintothe
thebody due
action ofto the action
body fluids of
andbody fluids [96].
enzymes and
enzymes
The [96]. The core–shell-structured
core–shell-structured carrier preparedcarrier prepared by poly(DL-lactide-co-glycolide)
by poly(DL-lactide-co-glycolide) (PLGA)-
(PLGA)-grafted modified
grafted modified
dextran showed adextran showed
fast drug releasea rate
fast in
drug
therelease
presence rate
ofin the presence
dextranase [97].ofLi
dextranase
et al. used[97]. Li et al.
ovalbumin
used
to ovalbumin
simulate to simulate
antigens antigensmodified
and grafted and grafted modifiedonto
ovalbumin ovalbumin onto
cationic cationic
dextran dextrandisulfide
through through
disulfide bonds. The prepared dextran-based nanogels can stably exist in the extracellular matrix.
When the concentration of GSH increased, the grafted ovalbumin was released in response. This
study verified the possibility of dextran nanogels being transported in target cells as antigenic drug
carriers [98]. Recently, a dextran-based conductive hydrogel was reported as a drug delivery system.
The dextran was modified by electroactive aniline trimer so that the hydrogel possessed stable
Int. J. Mol. Sci. 2020, 21, 9159 11 of 21

bonds. The prepared dextran-based nanogels can stably exist in the extracellular matrix. When the
concentration of GSH increased, the grafted ovalbumin was released in response. This study verified
the possibility of dextran nanogels being transported in target cells as antigenic drug carriers [98].
Recently, a dextran-based conductive hydrogel was reported as a drug delivery system. The dextran
was modified by electroactive aniline trimer so that the hydrogel possessed stable rheological property
and a controllable swelling ratio. Therefore, the release of drugs can also be precisely controlled by
electrical stimulation [99]. Wu et al. designed a carboxybetaine-modified dextran-polycaprolactone
(CB-Dex-PCL) micelle for biocompatible drug carriers. The results showed that the prepared drug
carrier has good protein antifouling function and could effectively prolong the circulation time of
drugs in the blood [100]. Dextran phosphate (DP) has high adsorption capacity and could react
with biologically active molecules. Solomevich et al. successfully prepared a pH-sensitive and
biodegradable DP hydrogel. After encapsulating prospidine (Pr), it could be used in controllable DDSs
(Figure 8) [101].
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 11 of 20

Figure 8.
Figure 8. Schematic
Schematic illustration
illustration of
of the
the synthesis
synthesis of
of dextran
dextran phosphate
phosphate (DP)–prospidine
(DP)–prospidine (Pr)
(Pr) hydrogels.
hydrogels.
Taken from [101].
Taken from [101].

4.4.
4.4. Alginate
Alginic
Alginic acid
acid isis mainly
mainly derived
derived from
from the
the cell
cell walls
walls of
of brown
brown algae
algae [102].
[102]. The
The unique
unique eggegg box
box
structure
structure and and chemical
chemical properties
properties make
make itit easy
easy to
to form
form gels
gelsininaqueous
aqueoussolution.
solution. Alginate
Alginate can
can form
form
hydrogel 2+2+,
hydrogel through intermolecular
intermolecularand andintramolecular
intramolecularcrosslinking
crosslinkingwithwith divalent
divalent metal
metal ionsions
(Ca2+(Ca
, Cu ,
Cu 2+ 2+ 2+
Zn ,, Pb
2+ Zn , ,etc.)
2+ Pb in , etc.) in aqueous
aqueous solution
solution [103].negatively
[103]. The The negatively
chargedcharged
alginatealginate can combine
can also also combinewith
with cationic
cationic drugdrug molecules
molecules through
through electrostaticinteraction.
electrostatic interaction.Alginate
Alginatenanoparticles
nanoparticles treated
treated with
with
hydrophobic
hydrophobic molecules
molecules such
such asas poorly
poorly hydrophobic
hydrophobic CS CS can
can form
form hydrophobic
hydrophobic nanocarriers
nanocarriers forfor drug
drug
delivery
delivery in in tumor
tumor tissues
tissues while
while maintaining
maintaining biocompatibility
biocompatibilityand and low
low cytotoxicity
cytotoxicity [104].
[104]. For example,
alginate-based
alginate-basedamphiphilic
amphiphiliccore–shell
core–shellnanoparticles
nanoparticles cancan
be used for the
be used for targeted delivery
the targeted of DOX
delivery of [105].
DOX
Tang
[105].etTang
al. prepared a phthalocyanine
et al. prepared (the second-generation
a phthalocyanine photosensitizer
(the second-generation (Pcs)) coupling
photosensitizer carrier
(Pcs)) coupling
by using
carrier bylow molecular
using weight weight
low molecular sodiumsodium
alginatealginate
(SA). SA, as an
(SA). SA,anionic polymer,
as an anionic could bind
polymer, couldtobind
the
to the highly expressed receptors (SR-A) on tumor-associated macrophages, allowing the Pcs to target
highly expressed receptors (SR-A) on tumor-associated macrophages, allowing the Pcs to target tumors.
tumors. Meanwhile,
Meanwhile, SA couldSA could significantly
significantly promote promote the dissolution
the dissolution of hydrophobic
of hydrophobic Pcs in solution
Pcs in aqueous aqueous
solution and does not require any surfactants, which greatly improves the treatment efficiency of
photodynamic therapy (Figure 9) [106].
Int. J. Mol. Sci. 2020, 21, 9159 12 of 21

and does not require any surfactants, which greatly improves the treatment efficiency of photodynamic
therapy (Figure 9) [106].
Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 12 of 20

Figure 9.9. (a)

Figure (a) Schematic
Schematic diagram
diagram ofof the
the design
design and
and synthesis
synthesis ofof aa novel
novel conjugation
conjugation vehicle
vehicle of
of aa
photosensitizer
photosensitizerbasedbasedononsodium
sodiumalginate
alginate(SA).
(SA).(b)
(b)In
Invivo
vivofluorescence
fluorescenceimages
imagesof
oftumor-bearing
tumor-bearingKM KM
mice
miceafter
afterintravenous
intravenousinjection
injectionof
ofSA-based
SA-basedcarriers
carrierswith
withdifferent
differentmolecular
molecularweights.
weights.The
Thered
redarea
area
represents
representstumor
tumorsites.
sites. (c)
(c)Ex
Exvivo
vivofluorescence
fluorescenceimages
imagesof oforgans
organsandandtumor
tumoratat24
24hhafter
afterinjection
injectionof
of
SA-based carriers with different molecular weights (1-SA1 is low-molecular-weight
SA-based carriers with different molecular weights (1-SA1 is low-molecular-weight SA-based SA-based carriers).
Modified
carriers). from [106].from [106].
Modified

4.5. Chondroitin Sulfate

4.5. Chondroitin Sulfate
Chondroitin sulfate is a glycosaminoglycan derived from animal cartilage. When interacting with
Chondroitin sulfate is a glycosaminoglycan derived from animal cartilage. When interacting
cancer cells, chondroitin sulfate can recognize and attach to the CD44 receptor, which can significantly
with cancer cells, chondroitin sulfate can recognize and attach to the CD44 receptor, which can
promote the uptake of chondroitin sulfate-based DDS by cancer cells. In addition, chondroitin sulfate
significantly promote the uptake of chondroitin sulfate-based DDS by cancer cells. In addition,
exposed to degrading enzymes (such as hyaluronidase) can be rapidly degraded, resulting in the
chondroitin sulfate exposed to degrading enzymes (such as hyaluronidase) can be rapidly degraded,
drug release of chondroitin sulfate-based DDS [107]. However, unprocessed chondroitin sulfate
resulting in the drug release of chondroitin sulfate-based DDS [107]. However, unprocessed
has excellent water solubility, and its direct use as a drug carrier will lead to low drug utilization.
chondroitin sulfate has excellent water solubility, and its direct use as a drug carrier will lead to low
Studies have shown that the conjugate system formed by cross-linking with chondroitin sulfate can
drug utilization. Studies have shown that the conjugate system formed by cross-linking with
significantly enhance the anti-tumor activity of hydrophobic drug molecules [108]. Compared with
chondroitin sulfate can significantly enhance the anti-tumor activity of hydrophobic drug molecules
the unprocessed chondroitin sulfate, the cross-linked chondroitin sulfate has lower hydrophilicity
[108]. Compared with the unprocessed chondroitin sulfate, the cross-linked chondroitin sulfate has
and better shielding effect, which can be used as a specific carrier for active drugs [21]. Combining
lower hydrophilicity and better shielding effect, which can be used as a specific carrier for active
chondroitin sulfate with CS, the amphiphilic polymer formed can self-assemble into micelles. Modified
drugs [21]. Combining chondroitin sulfate with CS, the amphiphilic polymer formed can self-
with FA and encapsulated with bortezomib, the prepared micelles have a uniform size distribution
assemble into micelles. Modified with FA and encapsulated with bortezomib, the prepared micelles
and can release drugs in response to the slightly acidic tumor microenvironment. The modification of
have a uniform size distribution and can release drugs in response to the slightly acidic tumor
microenvironment. The modification of FA gives micelles the ability to actively target tumors and
also promotes the uptake of drugs by tumor cells [109]. Liu et al. designed an amphiphilic polymeric
micelle on the basis of chondroitin sulfate using the self-assembly strategy (Figure 10). The reduction-
sensitive chondroitin sulfate A (CSA) was combined with deoxycholic acid (DOCA) through
Int. J. Mol. Sci. 2020, 21, 9159 13 of 21

FA gives micelles the ability to actively target tumors and also promotes the uptake of drugs by tumor
cells [109]. Liu et al. designed an amphiphilic polymeric micelle on the basis of chondroitin sulfate
using the self-assembly strategy (Figure 10). The reduction-sensitive chondroitin sulfate A (CSA) was
Int. J. Mol. Sci.with
combined 2020, deoxycholic
21, x FOR PEERacid
REVIEW
(DOCA) through disulfide bonds, and the therapeutic drug13DOX of 20
was encapsulated into the micelle simultaneously. The micelle released DOX in response under the
The micelle
high releasedofDOX
concentration in response
endogenous GSH, under the high
realizing concentration
specific treatment of of tumors
endogenous
[110].GSH, realizing
In organisms,
chondroitin synthase-1 (CHSY1) is an enzyme responsible for the synthesis of chondroitinenzyme
specific treatment of tumors [110]. In organisms, chondroitin synthase-1 (CHSY1) is an sulfate,
responsible for the synthesis of chondroitin sulfate, which is related to the occurrence
which is related to the occurrence of some tumors, especially those highly expressed in the colorectal of some tumors,
especially
area. those highly
The biopolymer expressed
delivery in combined
carrier the colorectal
witharea. The biopolymer
chondroitin sulfate hasdelivery carrier combined
a good targeting property
with chondroitin sulfate has a good targeting property in the delivery of anti-tumor
in the delivery of anti-tumor drugs. It could target drugs to the colon; deliver genes to the drugs.
tumorIt tissue;
could
target
and drugsthe
reduce toexpression
the colon; of
deliver
CHSY1,genes to the
which has tumor
a goodtissue; and reduce
therapeutic thecolon
effect on expression of CHSY1,
cancer [111].
which has a good therapeutic effect on colon cancer [111].

Figure10.
Figure 10.Illustration
Illustration of
of the preparation
preparation of
ofmicelle
micelledoxorubicin
doxorubicin(DOX)-loaded
(DOX)-loadedchondroitin
chondroitinsulfate A
sulfate
(CSA)-disulfide
A (CSA)-disulfide bond
bond(ss)-deoxycholic
(ss)-deoxycholicacid
acid(DOCA)
(DOCA)(CSA-ss-DOCA/DOX)
(CSA-ss-DOCA/DOX)andand the
the mechanism of
tumor cell.
action in a tumor cell. Modified from [110].

In recent years,
years, various
varioustypes
typesofofpolysaccharides
polysaccharides have
have beenbeen widely
widely used used as DDSs
as DDSs (Table
(Table 2).
2). HA
HA derived from the body itself could bind to the CD44 receptor upregulated
derived from the body itself could bind to the CD44 receptor upregulated by cancer cells, and has by cancer cells,
and has immunogenicity
immunogenicity that otherthat other polysaccharides
polysaccharides cannot matchcannot[79].match [79]. HA-mediated
HA-mediated DDSs haveDDSs have
the ability
the ability to
to actively actively
target, whichtarget, which can
can achieve achieve self-degradation
self-degradation by responding byto responding
environmental to environmental
changes [80].
changes
CS is rich [80]. CS is rich
in amino in amino
groups and cangroups and
easily becan easily bemodified.
chemically chemically modified.
CS-based DDS CS-based
is proneDDS is
to be
prone to be endocytosed
endocytosed by cancer cellsbydue
cancer
to itscells duetoto
ability its ability
adhere to celltomembranes
adhere to cellandmembranes and its low
its low immunogenicity
immunogenicity
[87]. The molecular [87].chain
The molecular
of dextranchain of in
is rich dextran is rich
hydroxyl in hydroxyl
groups, whichgroups, which isfor
is convenient convenient
chemical
for chemical modification.
modification. Dextran
Dextran is often usedistooften used to
construct construct
drug carriers drug
suchcarriers such as
as micelles micelles
[94] [94] and
and hydrogels
hydrogels [93].can
[93]. Alginate Alginate
chelatecan chelate polyvalent
polyvalent metal ions metal
to form ions to form for
hydrogels hydrogels for drug
drug carriers carriers
[103]. [103].
Similar to
Similar to HA, chondroitin sulfate can also recognize and bind to CD44
HA, chondroitin sulfate can also recognize and bind to CD44 receptor on cancer cells. Chondroitin receptor on cancer cells.
Chondroitin
sulfate-basedsulfate-based
DDS can beDDS can be effectively
effectively taken up taken up bycells.
by cancer cancer cells.In[107].
[107]. In addition,
addition, many many
other
other polysaccharides
polysaccharides such assuch as pullulan
pullulan [112] and [112] and heparin
heparin [113] have[113]alsohave
beenalso been developed
developed as DDSs, as DDSs,
showing
showing
excellent excellent
anti-tumor anti-tumor
properties. properties. The development
The development and utilization
and utilization of polysaccharide-based
of polysaccharide-based DDSs have
DDSs
shownhave shown advantages
significant significant advantages
in the field inof the fieldtherapy.
cancer of cancer therapy.

Table 2. Research progress of common polysaccharide-based DDSs.

Functionalization Characteristics of In Vivo

Name Design Strategy Reference
Method DDS Model
Preparation of drug-
Modification of
loaded polysaccharide- CD44 receptor
functional molecules
HA based hydrogels (HA- targeting and A549 cells [84]
(cholesteryl moiety and
based hydrogel biodegradable
methacrylate)
encapsulates DNase1)
Cross-linking between Modification of CD44 receptor B16F10,
HA [85]
Int. J. Mol. Sci. 2020, 21, 9159 14 of 21

Table 2. Research progress of common polysaccharide-based DDSs.

Functionalization Characteristics
Name Design Strategy In Vivo Model Reference
Method of DDS
Preparation of
drug-loaded
Modification of functional CD44 receptor
polysaccharide-based
HA molecules (cholesteryl targeting and A549 cells [84]
hydrogels (HA-based
moiety and methacrylate) biodegradable
hydrogel encapsulates
DNase1)
Cross-linking between
Modification of functional B16F10, A549,
polymeric electrolyte and CD44 receptor
HA molecules (HA itself as a H22, and HK2 [85]
ion (between HA and targeting
functional molecule) cells
DOX)
Anti-tumor
Constructing Modification of functional effect improved
CS polysaccharide–drug molecules (CS itself as a and systemic BEL-7402 cells [89]
conjugates (NCTD) functional molecule) toxicity
reduced
Constructing Modification of functional HepG2 and
CS polysaccharide–drug molecules (lactobionic pH-responsive SMMC-7721 [90]
conjugates (DOX) acid) cells
Self-assembly of
Introduction of cleavable Controlled MDA-MB-231
CS hydrophobic [91]
bonds (disulfide bond) release cells
polysaccharides
Constructing
polysaccharide–drug Introduction of cleavable
Dextran GSH-responsive D1 cells (DCs) [98]
conjugates (ovalbumin, bonds (disulfide bond)
OVA)
Preparation of
Molecular chain grafting
drug-loaded
(electroactive aniline
Dextran polysaccharide-based Electro-responsive L929 cells [99]
trimer hexamethylene
hydrogels (dexmethasone
diisocyanate)
or indomethacin)
Self-assembly of Modification of functional
Protein
Dextran hydrophobic molecules HeLa cells [100]
antifouling
polysaccharides (carboxybetaine)
Preparation of
pH-responsive
drug-loaded Modification of functional HeLa and
Dextran and anti-tumor [101]
polysaccharide-based molecules (phosphate) HEp-2 cells
effect improved
hydrogels (Pr)
Constructing Tumor-associated
polysaccharide–drug phagocyte
Modification of functional
conjugates targeting and J774A.1 and
SA molecules (SA itself as a [106]
(1-[4-(2-aminoethyl) photodynamic HepG2 cells
functional molecule)
phenoxy] zinc (II) therapy
phthalocyanine) improved
Self-assembly of pH-responsive
Chondroitin Modification of functional A549, HCT-116,
hydrophobic and tumor [109]
sulfate molecules (FA) and HT-29 cells
polysaccharides targeting
Self-assembly of
Chondroitin Introduction of cleavable
hydrophobic GSH-responsive HGC-27 cells [110]
sulfate bonds (disulfide bond)
polysaccharides

5. Conclusions and Perspectives

Both toxic side effects on the human body and the difficulties in overcoming the human body’s
physiological barriers of drug delivery (blood circulation, tumor accumulation, tumor tissue penetration,
endocytosis, and drug release) limit the utilization of traditional chemotherapy drugs. The proposal of
DDSs has opened up new prospects for the application of chemotherapy in tumor therapy. The technical
support of DDSs lies in the preparation of carriers with great performance. The development of
new materials or the modification of existing materials is the key to constructing efficient carriers.
As abundant and renewable resources in nature, polysaccharides have been proven to be ideal
materials in the construction of DDSs, which possess good biocompatibility and unique physicochemical
properties. Meanwhile, the application of polysaccharides to DDSs continues to have several challenges.
Int. J. Mol. Sci. 2020, 21, 9159 15 of 21

On the one hand, the molecular weight and structure of polysaccharides are affected by the season and
environment. Some polysaccharides lack solubility in some commonly used solvents, which limits
the chemical modification and drug-loading conditions. On the other hand, the form of interaction
between polysaccharides and drugs is varied. The design of polysaccharide-based DDSs is still in the
exploratory stage. It should be noted that many studies have simply evaluated the properties and
pharmacology of DDSs through in vivo and in vitro experiments; thus, the interactions between DDSs
and the human body, including absorption, distribution, metabolism, and excretion of the carrier in
the human body, need to be carefully studied. The design of DDSs based on polysaccharides should be
considered holistically. It is conceivable that polysaccharide-based DDSs with promising performance
and therapeutic effect that are fabricated in green and effective techniques will be soon applied in
clinical settings.

Author Contributions: Y.S. and X.J. contributed to writing of the manuscript and also in the preparation of the
original draft. Y.F. and X.M. contributed to visualization. H.H. contributed to reviewing and editing of the
manuscript. H.H. supervised. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the National Natural Science Foundation of China (51703105), the Natural
Science Foundation of Shandong Province (ZR2017BEM012), and the China Postdoctoral Science Foundation
(2018M630752).
Conflicts of Interest: There are no conflicts of interest to declare.

Abbreviations
DDS Drug delivery system
LRP Living radical polymerization
ROP Ring-opening polymerization
CMC Carboxymethyl chitosan
OSA Octenyl succinic anhydride
DOX Doxorubicin
GSH Glutathione
FA Folic acid
OCS Oxidized chondroitin sulfate
BSA Bovine serum albumin
CMs Chitosan-based microspheres
CRP Controlled living polymerization
PCL Polycaprolactone
PGA Polyglycolide acid
ATRP Atom transfer radical polymerization
HA Hyaluronic acid
PTX Paclitaxel
CS Chitosan
GC Galactosylated chitosan
NCTD Norcantharidin
GO Graphene oxide
REC Rectorite
DP Dextran phosphate
Pr Prospidine
SA Sodium alginate
DOCA Deoxycholic acid
CHSY1 Chondroitin synthase-1
HCLR HA/HAase/CS/liposome/shRNA
CD44 Cluster of differentiation 44
EPR Enhanced permeability and retention
IAP Silencing the inhibitor of apoptosis
CSA Chondroitin sulfate A
Int. J. Mol. Sci. 2020, 21, 9159 16 of 21

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