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Several properties of natural polysaccharides make them promising agents in the pharmaceutical sector for drug loading and delivery applications: (i) they can be obtained from reproducible plant materials, (ii) they can be manipulated by enzymatic and chemical methods, (iii) they are biocompatible, biodegradable, and have low immunogenic properties, (iv) they can be designed as stimuli-responsive (e.g., pH and ion-sensitiveness) drug delivery systems, (v) ionic polysaccharides are mucoadhesive, (vi) they can be conjugated or they can make complexes with bio-macromolecules, such as peptides and proteins, (vii) they can easily form gels, and (viii) they can form interpenetrated polymeric networks and semi-polymeric networks [4].

For the drug delivery, the gel structure forming property of polysaccharides are very attractive. Gels are 3D polymeric networks trapping a continuous liquid phase and thus they can be used to manage the release kinetics of embedded drugs [122]: the physicochemical properties of the polysaccharide gels (i.e., polymeric network chains trapping the huge amount of liquid) make them useful for the transportation and release of vaccines, proteins, peptides, and nucleic acid-based drugs [123]. By exhibiting high water‐retaining capacity, renewability, biodegradability, biocompatibility, and nontoxicity, polysaccharides offer ideal structures for hydrogel networks. Besides, these polysaccharides can be gelatinized and functionalized easily [4, 124]. A hydrogel is also a good drug delivery system because of its particular advantages in preventing drug degradation and thus avoiding obstacles such as short half‐life and poor water solubility [124].

Natural polysaccharides such as starch, cellulose, hyaluronic acid, and glycogen, have been engineered by using several methods such as chemical modification, co-polymer grafting, and atom transfer radical polymerization to obtain superior molecules for pharmaceutics [125]. For example, cellulose nanocrystals were grafted with polyethyl ethylene phosphate through the ring-opening polymerization and Cu(I)-catalyzed azide-alkyne cycloaddition by “click” chemistry approach, and this azide-tailored negatively-charged nanocrystals were encapsulated with the anticancer drug doxorubicin for targeting cancer cells [126]. In another study, the bioconjugation approach was used for targeted drug delivery: polyethylene glycol-conjugated hyaluronic acid nanoparticles have been developed to enhance selective entry of cytotoxic drugs into CD44, hyaluronic acid receptor over-expressing cancerous cells [127].

Natural polysaccharides can be also used in hydrogel form for drug delivery. For instance, as a complex branched glucan, dextran contains several numbers of hydroxyl groups that can be chemically modified with divergent functional groups to form hydrogels. Dextran hydrogels have been considered valuable vehicles for controlled drug release because of their biocompatibility along with flexibility and biodegradability. Besides, dextran hydrogels can form an extracellular matrix resembling 3D hydrophilic network structures that can be produced by either chemical or physical crosslinking approaches. In this 3D matrix structure, water molecules occupy the empty spaces between networks of polymer chains. To achieve a controlled drug release, drugs can be integrated into these dextran matrices [81]. Between the matrices suitable for the controlled drug release, a notable role is played by those systems that are capable of responding to the changes in the external environment. Dextran hydrogels can be modified to respond to changes in the pH and the ionic strength of the environment to alter network structure, swelling behavior, permeability or mechanical strength. Therefore, since pH values change along the gastrointestinal tract, pH-responsive dextran hydrogels can be particularly advantageous to be used in the gastrointestinal system to obtain a specific release [128].

Among many different polysaccharide polymers, gellan gum, a microbially derived polysaccharide, is drawing increased attention nowadays because of its favorable properties including abundance, nontoxicity, mucoadhesiveness, easy gelation, thermal and acid stability, and high transparency. Gellan gum has been suggested to be used for different purposes such as mucoadhesive or granulating agent, tablet binder, production of beads, films, microspheres and microcapsules, nanohydrogels, and nanoparticles [129]. For example, D’Arrigo et al. have designed a self-assembling nanohydrogel form based on gellan to deliver inactive prodrug prednisolone. This prodrug is processed into anti-inflammatory active drug prednisone in the liver. Since prednisolone is poorly soluble in water, it was chemically conjugated to the carboxylic groups of gellan and the hydrophobic moiety of prednisolone led to the self-assembly of nanohydrogels with an average size of about 300 nm with negative zeta potential values. This fabricated self-assembled gellan-based nanohydrogel was shown to enhance the solubility and cellular uptake of prednisolone [130]. Xanthan gum also meets the required properties for targeted delivery and controlled release of drugs in its nanoparticle, liposome, niosome, microsphere, hydrogel, dendrimer, or nanofiber forms. Because of its excellent flow properties, xanthan can stabilize many water-based systems. Besides, it remains effective over a broad range of pH, temperature, and ionic strength [81, 131]. When used alone or in combination with other macromolecules, such as cellulose derivatives, polyvinylpyrrolidone, karaya and guar gum, xanthan gum-based formulations have been shown to have a great ability to generate a drug release profile close to zero. On the other hand, the deacetylation of xanthan gum increases the negative charge of the polysaccharide to combine it with other biopolymers. Deacetylation also decreases the molecular weight and improves the solubility of xanthan gum; therefore makes the polysaccharide more preferable for pharmaceutical applications [132].

One of the novel drug delivery systems is microspheres. Microspheres contain dispersed drugs in a polymeric matrix structure and if it is modified properly for targeting the site of interest without untoward effects, they are reliable drug delivery systems for controlled release. Polysaccharides are abundant and cheap biopolymers and widely used as microsphere matrices to carry water-soluble model drugs. Polysaccharide-based microspheres of starch, chitosan, and alginate have been commonly used as biodegradable matrices to achieve controlled drug release [133]. For example, by using the emulsion solvent method, drugs can be loaded in alginate microspheres to obtain drug-loaded alginate microspheres. In this technique, the evenly mixed drug and alginate solution is emulsified under sonication followed by adding this mixture in a dropwise manner to an organic emulsion with constant stirring. The alginate-based microspheres can protect drugs from degradation as well as improve plasma half time for providing transport and release of drugs [45]. Some bioactive compounds, such as growth factors, can be denatured and lose their properties during the microsphere preparation steps: the organic solvent itself and also the presence of high shear stress can result in denaturation and therefore loss of biological activity of encapsulated proteins, including growth factors. To prevent this, microencapsulation technique, an attractive approach relies on the encapsulation of bioactive materials within a semipermeable polymeric membrane, can provide an alternative method to protect cells, drugs, small proteins, cytokines, growth factors or other bioactive compounds [45, 134]. Chitosan exhibits a good bio-adhesivity: it can bind to negatively charged mucosa cell surfaces very efficiently. This property makes it suitable for efficient drug adsorption. Furthermore, alginate/chitosan microcapsules have been shown to exhibit improved biocompatibility and mechanical strength for biomedical applications [134].

In recent years, polysaccharide-based nanoparticles have also attracted interest as therapeutic agent carriers. The functional groups of the polysaccharide backbone allow chemical modification to develop nanoparticles with diverse structures. Some polysaccharides can be recognized by specific cell types so, these polysaccharides can be used to design targeted-drug delivery systems through receptor-mediated endocytosis [135]. Alginate, fucoidan, carrageenan, laminarin, and ulvan are natural polysaccharides mainly isolated from seaweed and these biopolymers can be used to obtain nanoparticles with the desired shape, size, and charge after modified via different techniques such as covalent cross-linking, ionic linking, self-assembly, and polyelectrolyte complexing. Fucoidan is a polysaccharide with anti-tumor activities and so, various fucoidan-based nanoparticles have been designed to encapsulate anticancer drugs [136–138]. Huang et al. designed pH-sensitive nanoparticles for oral drug delivery to protect drugs from deterioration. Also, the composite nanoparticles obtained by using positively charged chitosan and negatively charged fucoidan through the ionic-gelation method were used for the delivery of anti-cancer drug curcumin. The encapsulation efficiency of curcumin in chitosan-fucoidan nanoparticles was higher than 85% and the release of curcumin from the nanoparticles was found to be increased at pH 6.0 and 7.0 [139].

Polysaccharide formulations can also be utilized in green pesticide technology by providing safer delivery of agrochemicals. Although agrochemicals enhance the crop yields, commonly used agrochemical formulations can contaminate the environment. The use of natural polysaccharides has been claimed to be used for the controlled-release of agrochemicals to reduce pollution and health hazards. Polysaccharides, in the structural forms such as micro- or nanoparticles, beads, or hydrogels, can reduce agrochemical leaching, volatilization, and degradation by providing slow release. For instance, while free chlorpyrifos is released in 1 day, 50% of the encapsulated insecticide chlorpyrifos is released in 5 days. Slow-release property of polysaccharide formulations can also enhance the water-holding capacity of the soil, besides polysaccharide-clay formulations can store ionic plant nutrients. In addition to protecting crops from pests and diseases, biopolysaccharide derived formulations can enhance infiltration rates, soil permeability and aeration, and microbial activity, and therefore enhance crop yield [140–142].

In the field of pharmaceuticals, nucleic acid delivery has gained increasing interest especially to be used for modulating cellular signals. For a safe and efficient intracellular delivery, nucleic acids have to be encapsulated in nanosized carriers. A novel process, termed caged nanoparticle encapsulation, has been developed for concentrated and unaggregated nucleic acid delivery by using hydrogels [143]. However, drug-loaded nanoparticles encounter numerous extracellular and intracellular barriers before arriving at the target site [144]. Many polysaccharides, like hyaluronic acid, alginate, and chitosan, are excellent bioadhesive materials. In addition, the presence of a dense layer of polysaccharides in a brush-like configuration on the nanocarrier surface can extend the circulation time of the carrier in the bloodstream before the clearance by mononuclear phagocyte system. Thus, the presence of polysaccharide in the nanostructure can also mitigate complement activation [144, 145]. Furthermore, in specific cell types, polysaccharides can be recognized by particular carbohydrate-binding cell-surface receptors, so polysaccharide moieties can provide targeted delivery for nucleic acids [146, 147]. For instance, dendritic-cell-associated C-type lectin-1 or dectin-1 receptor frequently expressed on antigen-presenting cells, thereby β-glucan containing nanoparticles can be used to treatment of inflammatory disorders which requires specific targeting to phagocytic cell types [144]. The other advantage of polysaccharides as carriers is they have various functional groups including hydroxyls, amines, carboxylic acids on the glycosidic units which can be easily modified. Thus, chemical modifications of polysaccharides have the potential to overcome specific obstacles of carrier systems such as insufficient nucleic acid binding, fast clearance by phagocytes and/or endosomal systems [144]. For example, although chitosan is an attractive polymer to use as a carrier for gene delivery, it is easily degraded by lysozymes or chitinases in the physiological environment thus, its transfection efficiency is very low. To overcome this limitation, derivatives of chitosan have been generated [143]. Galactosylated chitosan was shown to enhance the transfection efficiency of DNA and histidine-modified chitosan showed improved endosomal escape [148]. In another study, quaternized chitosan oligomers were reported as potential candidates for the delivery of DNA complexes because of their permanent positive charge [149]. Additionally, natural polysaccharides were also examined to investigate their RNA delivery potential. For instance, chitosan and hyaluronic acid, highly positively and negatively charged polysaccharides respectively, were studied as small interfering RNA (siRNA) carriers for gene silencing. Positively charged chitosan can stably interact with siRNA, therefore it can protect the nucleic acid from degradation but at the same time can also limit its release [150]. siRNA/chitosan complex was also shown to be prone to aggregation in the presence of serum proteins and also prone to be removed by the mononuclear phagocyte system [151, 152]. Lack of cell specificity, low stability at physiological pH, and weak buffering capacity are among the other limitations of chitosan-based delivery systems. However, anionic polysaccharides, like hyaluronic acid, usually require the presence of cationic components for more efficient interactions with siRNA. Besides, hyaluronic acid has the advantage that it can bind its specific receptors on certain cell types, therefore can provide targeted delivery. Accordingly, the development of carriers composed of both chitosan and hyaluronic acid can be advantageous for siRNA delivery whereby chitosan provides a strengthened siRNA binding while hyaluronic acid ensures high stability and targeting capacity [150].

Improvements in drug delivery systems affect various fields of medicine. The design and development of innovative materials to be used in contact lenses is a rapidly evolving discipline. These materials are developing alongside the progress made in related biomaterials [153]. In ocular pharmacology, there is a growing interest for the development of innovative delivery systems for a convenient and sustained drug release, especially for chronic eye diseases that require the adoption of a strict insurmountable treatment strategy for a large part of the affected population, as in the case of glaucoma [154]. New and improved contact lens materials can be used for drug delivery to the eye for more effective treatments [155]. For example, Xin-Yuan and Tian-Wei described a chitosan/gelatin composite film that was prepared by the solvent evaporation method. They showed that the presence of gelatin enhanced water absorption and oxygen and solute permeability of chitosan composite film. With its transparency, flexibility, and biocompatibility, chitosan/gelatin film structure was suggested as potential contact lens material [156]. Furthermore, drug delivery to the eye is currently a hot topic [155, 157]. Therefore, the use of natural polysaccharide derived materials should also be considered in the form of contact lenses to treat ocular diseases.

As discussed here, natural polysaccharides are promising candidates for drug delivery, as well as nucleic acid delivery. The design and development of polysaccharide-based targeted nanoplatforms have been gaining a great deal of attention. Future works seem to be focused more on chemical modifications of polysaccharides for designing efficient nanocarriers to be used in clinical trials. Although studies with polysaccharide-based nanosystems show promising proof of concept results, the ultimate performance of these platforms must be established in clinical trials. Besides, bringing the advantages of different polysaccharides together to achieve more efficient and biocompatible hybrid carrier systems has to be considered for successful drug delivery applications.