Advanced imaging approaches for dissecting the mechanisms of nose-to-brain drug delivery. From macro to nano scale.

Neurodegenerative disorders (NDs), such as multiple sclerosis (MS), involve the gradual decline of the central nervous system (CNS), with MS notably disrupting communication due to myelin loss. Treatments for MS and NDs include pharmacological, non-pharmacological, and invasive approaches, though challenges persist in drug effectiveness, tolerability, and CNS penetration. Biopharmaceuticals offer targeted therapies with fewer side effects, but their large size and complexity make administration difficult, especially across the blood-brain barrier (BBB). A promising method to bypass the BBB is nose-to-brain (N2B) delivery, where drugs are administered via the nasal cavity, in direct contact with the brain. This approach is particularly advantageous for large molecules like monoclonal antibodies, but bioavailability is still a challenge. Nanoparticles (NPs) are being investigated to enhance drug delivery by protecting drugs and allowing controlled release, though issues with stability, biocompatibility, and scalable production is a persistent difficulty. Another critical area of research is understanding how these drugs are distributed within the CNS after intranasal administration. Questions remain about which brain regions they reach, and the doses required to achieve therapeutic effects. This doctoral thesis aimed to unravel the underlying mechanisms of these distinct biological questions using advanced imaging techniques.