Nose-to-brain administration of cannabidiol-loaded polymeric micelles improves the core behavioral symptoms of autism spectrum disorder

Neurodevelopmental disorders including autism spectrum disorder (ASD) affect 5.9% of the global population. Research shows the potential therapeutic use of cannabidiol (CBD) to treat different neurodevelopmental disorders, including ASD. Intranasal drug delivery (i.n.) is a non-invasive and painless administration route that enhances drug bioavailability in the brain bypassing the blood-brain barrier. Various polymeric nanoparticles have been investigated for i.n. delivery with different success levels. In this study, we developed and characterized polymeric micelles of the poly(ethylene oxide)-b-poly(propylene oxide) block copolymer Pluronic® F127 loaded with 25% w/w CBD (based on solid weight) for nose-to-brain delivery in ASD. CBD-loaded polymeric micelles display a hydrodynamic diameter of 41 ± 1 nm by Intensity and 23 ± 1 nm by Number, as measured by dynamic light scattering, and very good compatibility and permeability in the human nasal septum cell line RPMI 2650, an in vitro model of the nasal epithelium. The accumulation of CBD-loaded polymeric micelles administered intranasally in the brain of ASD-like rats is confirmed by bioimaging. The CBD pharmacokinetics upon the i.n. (dose of 5 mg/kg) and oral (15 mg/kg) administration of the loaded polymeric micelles shows a 27.8% increase of the CBD concentration in the brain of ASD-like rats 20 min after i.n. administration, despite the 3-fold decrease in the dose. Finally, the efficacy of this nanoformulation to improve the core symptoms of ASD is demonstrated in behavioral studies in a behavioral model of the disorder in rats.