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Inhalation OctOber 2021 15 internalized by endocytosis. As such, lectins not only act as mucoadhesives, but can aid in delivering drug into cells (active cell-mediated drug uptake). Wheat germ agglutinin (WGA) is a lectin that spe- cifically binds to N-acetyl-D-glucosamine and sialic acid moieties and exists mostly as a heterodimer of 38,000 Da. Both N-acetyl-D-glucosamine and sialic acid are found in the nasal cavity, especially the olfactory mucosa. One of the benefits of WGA is its low potential for causing immunogenic reactions compared to other lectins, which may be powerful toxins (e.g., ricin). Poloxamer. Poloxamers are non-ionic, difunctional, triblock copolymers composed of a central hydro- phobic chain of polyoxypropylene between two hydrophilic chains of polyoxyethylene. Poloxamer gels are thermosensitive, exhibiting phase transitions from liquids (sols) to mucoadhesive gels upon expo- sure to the nasal temperature. e actual temperature of gelation can be adjusted by the addition of other excipients such as polycarbophil, polyethylene gly- col and benzalkonium chloride. One poloxamer of interest for nasal delivery, due to its low toxic- ity, high solubility and bioadhesive characteristics, is Poloxamer 407. eir comparatively low molecular weight and non-ionic nature makes poloxamers rel- atively weak mucoadhesive agents. To enhance their mucoadhesion and drug retention, a low concentra- tion (0.2-0.5%) of other mucoadhesive polymers, e.g., chitosan, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose or hydroxypropyl cellulose can be added to the poloxamer gel [24,28]. Polyacrylic acid. Polyacrylic acid is a synthetic, high-molecular weight polymer of acrylic acid. Mucoadhesion occurs through hydrogen bonding between the carboxylic acid functionality of the mucoadhesive polyacrylic acid and the sialic acid/ carboxylic acid groups of the glycoprotein compo- nent of mucus [28, 30-31]. Although these types of bonding forces are weak, numerous interaction sites lead to strong mucoadhesion. Polyethylene glycol. Polyethylene glycols (PEGs) are hydrophilic, water-soluble, polyether com- pounds. PEGs are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights. Polymer chain length plays an important role in mucoadhesion, with longer chain lengths leading to an increase in mucoadhesive properties. Having flexible polymer chains helps penetration and entanglement with the mucosal layer, thereby improving mucoadhe- sion [32]. In the case of PEG, a polymer of 20 kDa shows negligible mucoadhesive properties while one of 200 kDa has been shown to exhibit improved mucoadhesion and one of 400 kDa has excellent mucoadhesion [33]. iomers. iols are organosulfur compounds of the form R−SH, where the –SH functional group Gums. Other naturally occurring polysaccharides have also been shown to exhibit mucoadhesive prop- erties [24], including alginates, guar gum, pectin and xanthan gum. Alginates are salts of alginic acid, an anionic poly- mer obtained from brown seaweed. Alginic acid is a linear copolymer, comprising blocks of (1→4)-linked β-D-mannuronate and α-L-guluronate residues covalently linked in different sequences. ey form viscous gums and have good mucoadhesive prop- erties due to the presence of the carboxylic acid moiety, which causes hydrogen bonding with the glycoprotein of mucin. Guar gum is a non-ionic polysaccharide based on galactose and mannose units and is extracted from guar beans. It consists of a linear chain backbone of β(1→4)-linked mannose units to which galactose units are (1→6)-linked at every second mannose, forming short side-branches. e mucoadhesive properties of guar gum are due to hydrogen bonding with the mucin glycoproteins. Additionally, there is a synergistic rheological interaction between guar gum and xanthan gum—the viscosity of the gum combination is higher than the sum of the single polymer solutions. Pectin is a natural heterogenous anionic polysac- charide that is extracted from citrus peel or apple pomace. It contains linear chains of (1→4)-linked α-D-galacturonic acid residues that contain car- boxyl groups. e mucoadhesive properties of pectin come via the formation of hydrogen bonds between the carboxylic acid groups and mucin, and electro- static interaction between pectin and the mucin molecule. Mucin and pectin are both negatively charged; therefore, increasing the concentration of pectin in an aqueous medium increases electro- static repulsion with mucin. is repulsion causes uncoiling of the polymer chain, facilitating inter- penetration, entanglement and adhesion. Xanthan gum is an anionic polysaccharide pro- duced by the fermentation of glucose and sucrose. e xanthan molecule consists of a backbone of β(1→4)-linked D-glucose residues. Trisaccharide side chains containing two mannose units sep- arated by guluronic acid are linked to every other glucose unit. Although xanthan gum has negatively charged carboxyl groups on the side chains, the ste- ric hindrance of these side chains inhibits access to the charged mucin groups, leading to a low level of mucoadhesion [27]. Lectins. Lectins are carbohydrate-binding proteins that are capable of binding to specific sugar moieties [28, 29]. Due to their ability to cross-link sugar-con- taining macromolecules, they are able to coagulate these molecules, forming a thickened mass (agglu- tination). Certain lectins can bind to the mucosa, and then either stay on the cell surface or become