# Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery
## 4 Discussion
The positive zeta potential obtained for all formulations is evidence of the polysaccharide coating. Furthermore, using different chitosan types did not cause significant changes in the zeta potentials of both formulations, probably due of a similar degree of deacetylation (95%) [64]. Mucoadhesive polymers such as chitosan represent a significant strategy for overcoming the nasal drug delivery limits of low membrane permeability, short residence time, and mucociliary clearance. The presence of polysaccharides on the nanocapsule surface is expected to prolong the permanence of the formulation in the nasal cavity, open the tight junctions between the nasal epithelial cells, and promote drug permeation through the biological barriers, granting access to the CNS [65; 66; 67]. For these reasons, the evaluation of the ability of nanocapsules to interact with mucin is of great interest for nasal administration. Mucous membranes internally delimit the body cavities (stomach, esophagus, cornea, oral cavity, reproductive and respiratory tracts), and are characterized by a superficial mucus layer with protective and lubricating functions [68]. The mucus is composed of water (approximately 95%), lipids, inorganic salts, and mucin, a glycoprotein composed of \(N\)-acetylgalactosamine, \(N\)-acetylglucosamine, fucose, galactose, and sialic acid, which is responsible for the adhesive properties and the viscosity of the mucus [66]. Lipophilic drugs show an affinity for mucus glycoproteins, reducing their adsorption and the bioavailability. This issue, together with the drugs' poor aqueous solubilities, are limiting factors for the nose-to-brain delivery of lipophilic drugs. To improve the transport of SVT through this barrier, we used nanoparticles as a drug delivery system [69]. Our results showed how, for both formulations, particle size and MI increased with the increase in the mucin weight ratio, to a critical point. A previous study [50] has led to the conclusion that the nanoparticles in mucin solution form agglomerates in which the nanoparticles are the points of contact between negatively charged mucin chains. Beyond the critical value of the mucin ratio, the repulsive forces among the mucin chains break these agglomerates. Our results support this theory; nevertheless it has to be stressed that the decrease of MI observed for high mucin weight ratio does not indicate a decrease in the mucoadhesive capacity of the formulations [50]. However, the results indicate how in mucin excess, smaller aggregates are formed in order to minimize the repulsive forces between the chains of mucin, and to maximize the points of contact between the positive charges of chitosan and the negative charges of the mucin chains. Moreover, it was noticed that the critical point of the formulations was different for the nanocapsules coated with chitosan with different characteristics (LNC\({}_{\text{SVT-LMWchit}}\)\(f\) = 0.3 and for LNC\({}_{\text{SVT-HMWchit}}\)\(f\) = 0.55). This difference could be attributed to the different chain lengths of the two chitosan batches [63]. Indeed, in a previous study conducted with a different method, [PERSON] and co-authors proposed that mucin interacts mostly with high molecular weight chitosan [70]. On the other hand, the results presented in this paper, compared to similarly uncoated LNC, demonstrate a large increase in the mucoadhesive capacity, due to the presence of chitosan. The uncoated LNC showed values of MI = 1.4, PDI = 0.51, and a zeta potential of \(-9.5\) mV after contact with the maximum concentration of mucin (0.5% \(w/v\)) [71]. The PDI increase with the increase in the \(f\) mucin ratio corroborates the above-mentioned explanation. In fact, PDI results indicated that the heterogeneity of the distribution of the particle size in solution increased along with the mucin weight ratio, because of the formation of aggregates of different sizes.