Hyaluronic acid based-hybrid nanoparticles for targeted nose- to-brain delivery of dimethyl fumarate

Dimethyl fumarate (DMF) (Tecfidera®) is a first-line oral therapy for relapsing-remitting multiple sclerosis, but patients often discontinue it within 3 months due to gastrointestinal discomfort [1]. Nose-to-brain drug delivery could be advantageous in increasing DMF brain availability and avoiding gastrointestinal exposure. Herein, hybrid nanoparticles loaded with DMF (H-NPs) were prepared using phosphatidylcholine, palmitoylethanolamide (PEA), cholesterol, and poloxamer and hyaluronic acid (HA). The H-NPs compositions were as follows: L and LD (without PEA and HA), LP and LPD (with PEA but without HA), LH and LHD (with HA but without PEA), and LPH and LPHD (with both PEA and HA) at different concentrations. PEA, an endogenous lipid mediator, primarily activates peroxisome proliferator-activated receptor (PPAR)-α, exerting anti-inflammatory, metabolic, and neuroprotective effects. HA, known for its exceptional mucoadhesive properties, selectively binds to RHAMM receptors, which are often overexpressed in many inflammatory conditions [2]. H-NPs were made by a modified nanoprecipitation technique. Size, zeta potential (ZP), morphology, total drug in dispersion, viscosity, mucadesions and thermal properties were studied. For 30 days, the chemical stability of DMF in the H-NPs and the physical stability of all H- NPs were explored. In-vitro DMF permeation studies were carried out by the PermeaPad® system. RPMI 2650 and SK-N-BE2 cell lines were used to investigate LP and LPH cellular uptake. The stability of DMF in human and rat blood was determined by setting appropriate extraction and HPLC procedures. The mean size of nanoparticles statistically increased from 119 ± 1 nm of LP to 179 ± 4 of L at 219 ± 2 nm of LPH at 254 ± 2 nm of LH. Thus, HA and PEA influenced the physical properties of H-NPs. Also, the ZP has been most negative by HA and PEA addition: from -2,3 ± 1 mV of L to -17,3 ± 1 mV of LP to -25 ± 1 mV of LPH at -29.9 ± 1 mV of LH; TEM images proved that H-NPs were spherical but with irregular surfaces. Thermal analysis revealed the presence of HA on the H-NPs surface. The formulations showed great chemical-physical stability for 30 days. The total amount of DMF in dispersion was about 60%. H-NPs showed viscosity suitable for nasal administration regardless of HA presence. The permeation studies indicated that LHD and LPHD increased the amount of DMF permeated more than LPD and LD and free-DMF, evidencing the influence of HA on H-NPs performance. LP and LPH showed a rapid cell uptake at three hours. Compared to human blood, DMF appears immediately and totally degraded in rat blood, where it is partially hydrolysed to MMF. These results point to the potential use of H-NPs as viable nanocarrier candidates for encapsulating DMF for intranasal delivery and support the work in progress aimed at in vivo pharmacokinetic assessment. and support the work in progress aimed at in vivo pharmacokinetic assessment.