Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery

Abstract

Drug delivery to the brain represents a challenge especially in the therapy of central nervous system malignancies. Simvastatin (SVT), as other statins, has shown potential anticancer properties that are difficult to exploit in the CNS. In the present work the physico-chemical, mucoadhesive and permeability enhancing properties of simvastatin-loaded poly-ε-caprolactone nanocapsules coated with chitosan for nose-to-brain administration were investigated. Lipid-core nanocapsules coated with different molecular weight (MW) chitosans (LNCchit) prepared by a novel one-pot technique were characterized for particle size, surface charge, particle number density, morphology, drug encapsulation efficiency, interaction between surface nanocapsules with mucin, drug release and permeability across two nasal mucosa models. Results show that all formulations present adequate particle size (below 220 nm), positive surface charge, narrow droplet size distribution (PDI<0.2) and high encapsulation efficiency. Nanocapsules presented controlled drug release and mucoadhesive properties dependent on the MW of the coating chitosan. The results of permeation across RPMI 2650 human nasal cell line evidenced that LNCchit increased the permeation of SVT. In particular, the amount of SVT permeated after 4h for nanocapsules coated with low MW chitosan, high MW chitosan and control SVT was 13.91 ± 0.78 µg, 9.15 ± 1.23 µg and 1.42 ± 0.21 µg respectively. These results were confirmed by the SVT ex vivo permeation across rabbit nasal mucosa. This study highlighted the suitability of LNCchit as promising strategy for the administration of simvastatin for a nose-to-brain approach for the therapy of brain tumors.

Preparation and characterisation of PHT-loaded chitosan lecithin nanoparticles for intranasal drug delivery to the brain

“…18 Low molecular weight chitosan was used in this study, which has been reported to have a higher aqueous solubility, and short polymer chains that contributes to forming smaller particles compared to medium and high molecular weight chitosan. 25,33,34 The pH values of prepared NP suspensions were between 4.5 and 5.0, which is compatible with the biological pH of nasal mucous, and in agreement with previous study. 32 In the present study, the ADS and zeta potentials of the prepared NPs were highly dependent on the amount of chitosan used.…”

“…Moreover, NPs size also plays an important role in contouring drug release from NPs. 25 The release studies concluded aer 24 hours before reaching total PHT release. This behaviour was previously reported with encapsulated tamoxifen, which showed an extended release rate from chitosan-lecithin NPs even aer 120 hours.…”

“…54 Additionally, the positive charge and mucoadhesive properties of chitosan, could also facilitate the direct entry to the brain through the nasal mucosa as previously demonstrated. 25,55 For example, carboxymethyl chitosan NPs were used as a carrier to deliver carbamazepine via the IN route. The data showed statistically higher amounts of carbamazepine in the brain when it was delivered encapsulated within carboxymethyl chitosan NPs versus that which was administered as a solution.…”

“…The mucoadhesive properties are important to avoid mucociliary clearance and increase residence time in the nasal cavity by the electrostatic interaction between the positively charged amine groups of D-glucosamine molecules of chitosan and the negatively charged sialic acid residues of mucin. 25 On the other hand, the positive surface charge is a good indicator that the chitosan was present at the external interface of the NPs. As a result, smaller aggregates will be formed due to the repulsive positive forces between the NPs.…”

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“…The permeation-enhancing property of chitosanis due to its mucoadhesive property and its ability to transiently open the tight junctions in the nasal mucosa 10 . Histological study also confirmed that chitosan does not lead to any significant histological changes in nasal mucosa 11 .…”