Chitosan-coated lipid nanocapsules for nose-to-brain delivery in the scope of multiple sclerosis

Details

Supervisors

des Rieux, Anne

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences pharmaceutiques

Abstract

Central Nervous System (CNS) bioavaility of drugs is a limiting factor for treatments of CNS diseases such as Multiple Sclerosis (MS). Intranasal delivery allows nose-to-brain delivery (N2B) bypassing the Blood-Brain Barrier (BBB). N2B delivery can be improved by encapsulating the drugs in nanoparticles and modifying their surface. Here, this modification is made possible by the use of a polymer derived from chitin, chitosan (CS). It has charge-dependent mucoadhesive properties which can lead to an increase in the residence time of the formulation in nasal cavity and in the permeation of the nanoparticles. CS is adsorbed on lipid nanocapsules (LNC). In the first phase of this project, the formulation of LNC CS was optimised to present nanoparticles that are both stable for one week and positively charged. As CS positive charges are influenced by the pH, CS solution at pH 5.5 was the best compromise between physiological tolerance and obtention of positive zeta-potential. The mucoadhesive properties of the LNC CS were then evaluated. Mucoadhesion assays were performed using a mucin solution and confirmed those properties. In a second part, in vitro cell viability tests were carried out. While it was observed that CS did not alter the viability of olfactory cells, it was found to be toxic for microglial cells. The toxicity observed on microglial cells could be explained by the immunomodulatory properties of CS or by its positive charges. These cells are already activated in MS. In vivo brain biodistribution was evaluated in a third and final step. CS coating did not increase the bioavailability of CNS in the brain. Overall, it can be concluded that the LNC CS were toxic for brain cells and did not show any evidence of improvement in N2B transport. The hypotheses put forward to explain this lack of increased transport could be justified by lack of mucoadhesive properties or by nonspecific binding to the mucosa, downstream of the olfactory region. Therefore, LNC CS formulated did not meet the project's objective and, moreover, presented a particularly worrying toxicity risk in the context of MS. In perspective, odorranalectin used as a surface modifier could be an interesting alternative. This olfactory specific binder could increase the transport of N2B.