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

Abstract

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)-<i>b</i>-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 <i>in vitro</i> 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.