# Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery
## 4 Discussion
The oligosaccharideschain's of mucin glycoproteins presenting terminal sialic acid residues confer a negative charge to the molecule; therefore, the variation of the particle zeta potential from positive to negative values demonstrates how the mucin enrobes the nanocapsules interacting with their surface layer of chitosan. This suggests that mucoadhesion mechanism is driven by the electrostatic interaction of the positively charged amine groups of d-glucosamineamine molecules of chitosan with the negatively charged sialic acid residues of mucin [72]. The SVT-loaded lipid core nanocapsules formulation was able to control drug release, due to the two diffusional barriers: the PCL polymer wall and the lipid dispersion present in the nanocapsule core. The nanoencapsulation reduced the diffusion rate of SVT across a dialysis membrane, confirming data that is frequently described in the literature as a property of polymeric nanoparticles [33]. Regarding the comparison between the two formulations, LNC\({}_{\text{SVT-HMWchit}}\) afforded better control of drug release. In order to explain the different release profiles, we evaluated the differences in terms of their physicochemical properties. Firstly, this can be explained by the higher viscosity of the chitosan used to develop the LNC\({}_{\text{SVT-HMWchit}}\). Previous studies demonstrated that the viscosity of the chitosan is an important factor for modulating the release control [73]. Moreover, nanoparticle size can influence in the release profile, which increases with decreasing particle size. Indeed, LNC\({}_{\text{SVT-LMWchit}}\) had a lower mean particle diameter than LNC\({}_{\text{SVT-HMWchit}}\), which could contribute to explaining their different release profiles, because of the greater available surface area [74; 75]. The permeation across the RPMI 2650 human nasal cell line showed that the SVT transported across the nasal cell model by LNC\({}_{\text{SVT-LMWchit}}\) and LNC\({}_{\text{SVT-HMWchit}}\) can enhance drug transport across a cell pseudo-monolayer that also secretes mucin on its apical surface. The increase of SVT permeation across the human nasal cell layer can be explained by different mechanisms. In literature, chitosan is associated with an opening of tight junctions that increase cell layer permeability. However, this mechanism generally favors the permeation of water-soluble drugs, and it has been evidenced that it is slightly less efficient for chitosan bound to nanoparticles, compared to simple polysaccharide solutions [76]. More recently, it has been demonstrated that the biodegradation of nanocapsules by enzymes in the mucus barrier or intracellularly could be pivotal in enhancing the transcellular transport of lipophilic drugs [77]. The results of the ex vivo permeation studies on rabbit nasal mucosa confirmed and further added evidence for the fact that the nanoencapsulation of SVT significantly increased its permeation across excised nasal mucosa. In this case, the higher permeation evidenced for LNC\({}_{\text{SVT-LMWchit}}\) could be explained by a combination of factors. The smaller particle sizes of nanocapsules coated with low molecular weight chitosan could have facilitated its absorption into the mucosal tissue as reported before [78]. Moreover, an important factor is the bioadhesion of the nanostructures, as previously explained, given by the particles shell of chitosan, which interacts with electrostatic forces at the anionic sites of the nasal mucus [65]. However, from the mucoadhesion data, a better interaction with mucus could be expected from nanocapsules coated with the high molecular weight chitosan. However, the slower release kinetics evidenced for these particles have probably contributed to limiting the amount of drug permeated, especially considering that drug accumulation into the tissue is superimposable for the two nanocapsule formulations. Previous findings [79; 80], agree that chitosan-coated nanoparticles increase drug permeation across the nasal mucosa, compared to the free drug control.