# Mucoadhesive Hydrogel Nanoparticles as Smart Biomedical Drug Delivery System
## 6 Mucoadhesion and Its Relation with Certain Polymers  
Several approaches have been designed to optimize hydrogel with bio-adhesive properties to overcome the issue of mucosal penetration and improve gastro-intestinal tract uptake [37]. Such properties can be obtained by using marine mussels incorporating the catechol moiety 3,4-dihydroxy-L-phenylalanine (DOPA) in hydrogels to promote bio-adhesion [38]. Bio-adhesion may also be improved by the interconnection of polymers having mucoadhesive properties such as chitosan, hyaluronic acid, polygalacturonic acid (pectin), alginate, and poly(acrylic acid) (Table 3) [39]. Additionally, lectin proteins canfurtherincrease the adherence of microparticles to the intestinal epithelium and enhance the penetration of drugs. Recently, lectins have been incorporated into nanoparticle moieties as a targetedtherapy that can bind to carbohydrate moieties attached to glycoproteins expressed on the surface of cancer cells [40]. Thiolated polymers have also emerged as a promising approach that can be used for mucoadhesion and muco-penetration in drug delivery [41]. The advantage of thiolated polymers is the ability of their free thiol groups to bind with cysteine domains in mucin [42]. The inter- and intramolecular disulfide bonds that form between mucin and thiol groups, can lead to relatively improved stability, prolonged residence and disintegration time in the mucus, and more sustained drug release [43]. Various thiolated polymers include chitosan-iminothiolane, poly(acrylic acid)-cysteine, poly(acrylic acid)-homocysteine, chitosan-thioglycolic acid, chitosan-thioethylamidine, alginate-cysteine, poly(methacrylic acid)-cysteine, and sodium carboxymethylcellulose-cysteine [44]. It is demonstrated that chitosan adheres to mucosal surfaces within the body [45] and canopen tight junctions between epithelial cells even through well organized epithelia [46]. The electrostatic interaction between the positively charged amines on chitosan polymer chains (pKa = 6.5) and the negative sialic acid residues on the glycoproteins in mucosal fluid plays a role in the mucoadhesive properties of chitosan [47]. Moreover, chitosan possesses NH\({}_{2}\) groups that can react with mucin forming electrostatic interpenetration [48]. \begin{table}
\begin{tabular}{c c c c} \hline \hline \multirow{2}{*}{**Theory**} & **Chemical and Physical Reaction** & **Biological Reactive System** & **Result** \\ \hline \multirow{2}{*}{Electronic theory} & Electron transfer reaction & Mucus and the mucoadhesive system & Electrical double layer of charges at the mucus and mucoadhesiveinterface \\ \hline \multirow{2}{*}{Adsorption theory} & Hydrogen bonding reaction & Mucus and the mucoadhesive system & Adhesive interaction between the substrate surfaces \\ \hline \multirow{2}{*}{Diffusion theory} & \multirow{2}{*}{Adhesive force} & Mucus and the mucoadhesive system & Interpenetration of both polymer and mucin chains to a sufficient depth \\ \hline \multirow{2}{*}{Wetting theory} & \multirow{2}{*}{Spreading property} & Mucus and the mucoadhesive system & Attachment regarding to contact angle \\ \hline \multirow{2}{*}{Fracture theory} & Detachment of polymer moieties & Mucus and polymer moieties & Relates the force for polymer detachment \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Theories of mucoadhesion. Polygalacturonic acid (PgA) is a natural polymer with a heterogeneous structure bonded via \(\alpha\) (1,4) glycosidic linkage. [PERSON] and his colleagues have demonstrated that PgA has limited dissolution in distilled water, Phosphate buffer saline (pH7.3), and acidic distilled water (pH3), resulting in white turbidity (Figure 3) [49]. This result is consistent with its hydrophobic properties [50]. PgA is not degraded in the upper gastrointestinal tract due to its insolubility in acidic conditions [51]. However, PgA can be dissolved in alkaline distilled water (pH 10), exhibiting a translucent yellow-green color. This means it can be hydrolyzed in the high pH environment of the colon.