Next-generation hybrid nanosystems for cannabidiol: From molecular challenges to site-specific preclinical applications.

Cannabidiol (CBD) is a monoterpene phenolic compound extracted mainly from Cannabis sativa, which is produced in high amounts compared to other plants. The compound is regarded as a promising therapeutic agent with anti-inflammatory, analgesic, and neuroprotective effects for biomedical use. Furthermore, important advances have been obtained in dermatological and anticancer effects. Nowadays, the major challenges to the development of new medicine based on CBD arise from its unfavorable physicochemical properties that include reduced solubility in aqueous media (∼0.01 mg/mL), significant degradation due to first-pass metabolism, very low oral bioavailability (typically 6-20%), and an adverse pharmacokinetic profile. Seeking to overcome these disadvantages, recent studies have focused on employing delivery systems, including liposomes, polymeric nanoplatforms, and inorganic nanoparticles, which have attracted considerable attention for their excellent biocompatibility, high encapsulation capacity, and controlled-release properties. Although conventional single-nanoplatforms offer advantages such as a large number of potential applications, they also have serious drawbacks, including burst drug release and short-term instability. Therefore, with respect to systems that will possess improved properties, hybrid nanoparticle systems have emerged as a second-generation class of systems capable of encapsulating CBD and potentially providing characteristics not available from single-nanoparticle systems. These include higher load efficiencies and stability, controlled and targeted delivery profiles, lower levels of premature drug release and greater enhancement of bioavailability. They are further able to provide site-specific delivery (i.e., transdermal, oral, or CNS-targeted). The aim of this review is to provide readers with a simple summary of the most recent information found within the literature concerning CBD-loaded hybrid nanoparticle systems. It also discusses current preclinical evidence, translational challenges, and future perspectives for the clinical development of these systems.