Abstract
BACKGROUND AND OBJECTIVE: Delivering therapeutic drugs to the brain for neurological disorders remains challenging due to the restrictive nature of the blood-brain barrier (BBB). Intranasal (IN) nanoparticle delivery may enhance the bioavailability of lipophilic cannabidiol (CBD), addressing limitations associated with systemic administration. METHODS: Further optimization of nanoparticle properties is necessary to enhance brain uptake and therapeutic potential for neurological disorders. Following IN administration of the nanoformulation, C57BL/6 male mice (3-6 months old, n = 4/group) were euthanized at 2, 4, and 8 h. Plasma, olfactory bulb (OB), hippocampus (HP), striatum (STR), and cortex (CTX) were collected and analyzed for CBD and 7-COOH-CBD using liquid chromatography-mass spectrometry (LC-MS). Two-way analysis of variance with Tukey's multiple comparisons was used for statistical analysis. RESULTS: CBD levels in the brain peaked at 4 h (5788 ng/mg), while 7-COOH-CBD reached its highest concentration at 2 h (3080 ng/mg). In plasma, maximum CBD levels were detected at 4 h (797 µg/mL), whereas 7-COOH-CBD peaked at 2 h (893 µg/mL). Despite measurable brain penetration, only 0.12% of the administered dose reached brain tissue, with 15.94% retained in plasma. CONCLUSION: This is the first study to provide the quantification of CBD and its 7CBD-COOH in various brain regions following IN administration of a CBD nanoformulation. While the approach facilitated brain delivery, overall bioavailability remained low. The use of four mice per group is a limitation that may impact the internal validity of these findings. This study aimed to develop a novel hydrophilic CBD nanoformulation for IN delivery and quantify its distribution and its major metabolite, 7-carboxy-cannabidiol (7CBD-COOH) in distinct brain regions and in plasma of mice.This methodology has the potential to overcome the limits of conventional CBD administration, providing a more effective treatment strategy for targeting brain diseases.