From Screening to a Nanotechnological Platform: Cannabidiol–Chemotherapy Co-Loaded Lipid Nanocapsules for Glioblastoma Multiforme Treatment

<b>Background/Objective</b>: Cannabidiol (CBD) has gained increasing interest due to its multifaceted anticancer properties and favourable safety profile. Glioblastoma multiforme (GBM), a highly aggressive brain tumour with limited treatment options, represents a compelling target for CBD-based therapies. In this study, we report the rational design of two distinct formulations of lipid nanocapsules (LNCs) co-encapsulating CBD and a chemotherapeutic agent, tailored for intracranial and systemic administration. <b>Methods</b>: The cytotoxicity of various CBD-chemotherapeutic combinations, including temozolomide, carmustine, doxorubicin, and paclitaxel (PTX), were screened in vitro in U-87 MG and U-373 MG human GBM cell lines and analyzed for chemical compatibility. Moreover, the efficacy and the anti-migratory effect of the selected combination was further assessed in ovo and in vitro, respectively. Lastly, two LNC formulations coloaded with the selected combination were prepared in two different sizes via the phase inversion temperature method. <b>Results</b>: First, CBD in solution exhibited potent cytotoxicity and significantly inhibited cell migration in both GBM cell lines. Among the CBD-chemotherapeutic combinations tested, only CBD + PTX demonstrated both additive/synergistic interaction and favourable chemical compatibility. Second, this enhanced effect was confirmed in ovo. Third, the CBD + PTX combination also exhibited anti-migratory effect. Finally, two co-loaded LNC formulations-51.2 ± 0.9 nm and 25.9 ± 0.3 nm in size-were developed for intracranial and systemic delivery, respectively. Both formulations exhibited high monodispersity, a slightly negative ζ-potential, and consistently maintained a 7.5:1 CBD:PTX mass encapsulation ratio across both particle sizes. <b>Conclusions</b>: CBD + PTX co-loaded LNCs represent a promising and versatile nanomedicine platform for GBM therapy.