**5. Polysaccharide-based materials in drug delivery**

Many properties of polysaccharides such as biocompatibility, solubility, potential for modifi‐ cation, and innate bioactivity provide great potential for their use in drug delivery systems (Figure 3).

**Figure 3.** Properties of polysaccharides for potential use in drug delivery systems

Despite many synthetic polymers, polysaccharides have very low or no toxicity levels [97-100]. For example, dextrans are biopolymers composed of glucose with α-1,6 linkages, with possible branching from α-1,2, α-1,3, and α-1,4 linkages, that exhibit low toxicity and high biocompatibility, that makes them biocompatible hydrogels for controlled prolonged therapeutic release [101] and microspheres with no inflammatory response following subcutaneous injection into rats [102]. Since polysaccharides are naturally present in the body, most of them are degraded enzymatically. Through enzyme catalysis, polysaccharides can be broken down to their monomer or oligomer building blocks and recycled for use as storage, structural support, or even cell signaling applications [103]. As a result, mechanism of release for therapeutics associated with polysaccharide-based carrier systems is provided by enzymatic degradation [104].

Edwards et al. identified a mannan:galactosyltransferase (GalT) in *Trigonella foenum*-*graecum* [94], an enzyme that facilitates mannan *O*-acetylation. However, discovery of the involvement of a large plant-specific family of Trichome birefringence-like (TBL) proteins in *O*-acetylation of wall polymer as specific *O*-acetyltransferases suggested that this gene family encompassed a mannan *O*-acetyltransferase [95]. A highly expressed (among the 10 most abundant ESTs) homolog of *At*TBL25 in the *Amorphophallus konjac* deep sequencing database [96] revealed that this protein or the closely related *At*TBL26 could represent mannan *O*-acetyltransferase(s) in

Many properties of polysaccharides such as biocompatibility, solubility, potential for modifi‐ cation, and innate bioactivity provide great potential for their use in drug delivery systems

Despite many synthetic polymers, polysaccharides have very low or no toxicity levels [97-100]. For example, dextrans are biopolymers composed of glucose with α-1,6 linkages, with possible branching from α-1,2, α-1,3, and α-1,4 linkages, that exhibit low toxicity and high biocompatibility, that makes them biocompatible hydrogels for controlled prolonged therapeutic release [101] and microspheres with no inflammatory response following subcutaneous injection into rats [102]. Since polysaccharides are naturally present in the body, most of them are degraded enzymatically. Through enzyme catalysis, polysaccharides can be broken down to their monomer or oligomer building blocks and recycled for use as storage,

**5. Polysaccharide-based materials in drug delivery**

**Figure 3.** Properties of polysaccharides for potential use in drug delivery systems

*Arabidopsis* [95].

318 Application of Nanotechnology in Drug Delivery

(Figure 3).

The functional groups of polysaccharides such as hydroxyl and amine groups yield high aqueous solubility. However, this solubility can often be adjusted via monomer modification. For example, *O*-acetylation of glucomannan can be used to modulate the formation of intermolecular hydrogen bonds with water, thereby altering aqueous solubility [105].

Due to the presence of various derivable groups on molecular chains, polysaccharides can be easily modified chemically and biochemically, resulting in many kinds of polysaccharide derivatives. These modifications can change the character of the polysaccharides. For instance, hydroxyl group oxidation enhances biodegradability, while sulfonation generates a heparinlike polysaccharide with increased blood compatibility [106]. Quaternization of the primary amines with various alkyl groups can be used to enhance solubility and alter bioactivity [107-109].

Many polysaccharides possess innate bioactivity, particularly mucoadhesive, antimicrobial, and anti-inflammatory properties. Positively charged polysaccharides are capable of binding to the negatively charged mucosal layers through charge interactions [110-112]. For neutral or negatively charged polysaccharides, hydrogen bonding provides an alternative mechanism for mucoadhesion [113]. Nanoparticle carriers made of bioadhesive polysaccharides could prolong the residence time and therefore increase the absorbance of loaded drugs [114]. Several polysaccharides are also antimicrobial in nature, such as chitosan [115]. Other polysaccharides are known to reduce inflammation. Anti-inflammatory activity is thought to be due to binding with immune-related acute phase and complement proteins [111,116] and polysaccharides are known to interact with a variety of proteins.

Nanocarriers are nanoparticle drug delivery systems that are used to deliver drugs or biomo‐ lecules. Nanocarriers are sub-micro particle structures smaller than 100 nm in at least one dimension and cover nanospheres, nanocapsules, nanomicelles, nanoliposomes, and nano‐ drugs, etc. Nanoparticle drug delivery systems have noticeable advantages. Due to the ultratiny volume of nanoparticle they can pass through the smallest capillary vessels and avoid rapid clearance by phagocytes, that lead to greatly prolonged duration in blood stream. Due to small dimensions, nanocarriers are able to cross the blood-brain-barrier (BBB) and operate on cellular level. They can easily penetrate cells and tissue gap to arrive at target organs such as spleen, spinal cord, liver, lung, and lymph. Because of the biodegradability, pH, ion and/or temperature sensibility of materials, they could show controlled release properties. They can improve the utility of drugs and reduce toxic side effects; etc. As drug delivery system, nanocarriers can entrap drugs or biomolecules into their interior structures and/or absorb drugs or biomolecules onto their exterior surfaces. Presently, nanoparticles have been widely used to deliver drugs, polypeptides, proteins, vaccines, nucleic acids, genes and so on.

In recent years, a large number of studies have been conducted on polysaccharides and their derivatives for their potential application as nanoparticle drug delivery systems [114,117-120] and among them, mannan is a very promising bioactive material for drug nanocarrier systems since an amphiphilic form of mannan can spontaneously incorporate proteins and other agents, potentially providing a new nanostructure drug delivery system.

since the non-phagocytic cell line was not affected and internalization was confirmed with J774. The high nanogel toxicity observed with the macrophage cell line indicated that the cell line J774 was not suitable for studies with mannan-C16 nanogel and primary cultures of

Mannan as a Promising Bioactive Material for Drug Nanocarrier Systems

http://dx.doi.org/10.5772/58413

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In 2012, the mannan nanogel cytocompatibility was tested in mouse embryo fibroblast cell line 3T3 and mouse bone marrow-derived macrophages (BMDM). [12]. The essential focus of the study was to assess nanomaterial cytocompatibility and to analyze the internalization by macrophages. The results of this study indicated that the mannan nanogel was biocompatible to mouse embryo fibroblast 3T3 cells and mouse BMDM. Essentially, no cytotoxic effect was observed with mannan nanogel up to about 0.4 mg/mL in *in vitro* experiments. Cell survival rate only dropped significantly at higher tested concentration after 48 h of incubation. Comet assay, under tested conditions, revealed no DNA damage in mouse embryo fibroblast 3T3 cells but possible DNA damage in mouse BMDM. Upon internalization by mouse BMDM mannan nanogel was localized in vesicles, as judged by the non-even distribution over the cytoplasm, and concentration of the fluorescence in internalized structures. Exit of nanogel from the mouse BMDM was observed when cells were incubated in fresh medium. Confocal colocali‐ zation image analysis denoted that the entrance and exit of nanogel and FM 4-64 might occur

Sato et al. [127] examined the adhesion inhibitory effect of mannan coating on acrylic denture surfaces against *Candida albicans* and *Candida glabrata*. The outermost layer of the *Candida* cell wall is covered with hydrophilic polysaccharides, such as mannan or galactomannan [128]. These mannans on the fungal surface function as adhesins, which are involved not only in the adhesion to the host cell [129,130] but also in the adsorption to plastic plates. On the other hand, when the plastic surfaces of culture dishes were coated with mannan, the adherence of *C. albicans* to the dishes was significantly inhibited [131,132]. The results of this study indicated that mannan inhibited the adhesion of *Candida* in a concentration-dependent manner, but mannose was not able to inhibit *Candida* adhesion even at a high concentration. The application of 0.1 mg/mL of mannan coating overnight showed inhibitory effects on the adhesion of the hyphal form of *C. albicans.* In the case of *C. glabrata*, the inhibitory effect was also observed to occur in a concentration-dependent manner, and the 10 mg/mL of mannan led to significantly higher anti-adhesive effects. This indicated that mannan effectively prevented the adhesion of two major *Candida* species to the denture surface, indicating the possibility of applying such

Superparamagnetic iron oxide nanoparticles (SPIONs) have been used as a contrast agent in magnetic resonance imaging (MRI) or as a carrier platform in the applications of drug [133-135] and gene delivery [137,138]. It was previously reported that mannan-coated SPION (mannan-SPION) could be specifically targeted to macrophages by the interaction with mannose receptors on antigen-presenting cells (APCs) [139]. Vu-Quang et al., [10] investigated the physicochemical properties, the *in vitro* and *in vivo* uptakes of carboxylic mannan-coated SPION (CM-SPION) using MRI and assessment of systemic toxicity. Results of the study showed that CM-SPION achieve longer circulation than mannan-SPION without compromis‐ ing specificity. The intracellular accumulation of CM-SPION in macrophages was higher than

macrophages that do not exhibit cytotoxicity should be used instead.

by the same processes – endocytosis and exocytosis – in BMDM.

a coating for clinical dentistry.
