Hyaluronic acid-based hybrid nanoparticles for intranasal delivery of dimethyl fumarate

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease characterized byan abnormal reaction of defenses of the immune system attaking certain nervous system components. Dimethylfumarate (DMF) is the first-line oral therapy for relapsing-remitting MS. After oral administration, DMF is rapidly metabolized to monomethylfumarate (MMF). Intranasal drug delivery may offer a potential solution for increasing the brain availabilityof DMF and avoiding gastrointestinal exposure. With this purpose, hybrid nanoparticles based on hyaluronic acid (HA) with or without palmitoylethanolamide (PEA) were designed and characterised. PEA, an endogenous lipid mediator, primarily activates peroxisome proliferator-activated receptor (PPAR)-α, exerting anti-inflammatory, metabolic, and neuroprotective effects. HA and PEA exert a significant influence on the size, PDI and zeta potential of the nanoparticles, whereas the drug content was independ on their composition. The nanoparticles exhibited a spherical shape, although their surfaces were irregular. Stability studies in blood studies have shown that in contrast to human blood, DMF is rapidly and completely degraded in rat blood, where it is partially hydrolysed to MMF. The nasal administration to rats of the raw DMF did not allow to detect DMF and MMF in both the bloodstream and cerebrospinal fluid. On the contrary, the nasal administration to rats of LHD and LPHD allowed to detect DMF and MMF in cerebrospinal fluid, but not in the bloodstream. HA-based hybrid nanoparticles hold significant promise as novel carriers for the intranasal administration of DMF in the treatment of MS.