Improved drug delivery across the blood-brain barrier through post-insertion functionalization of lipid nanocapsules...

Crossing the blood-brain barrier (BBB) remains a major challenge in drug delivery for central nervous system (CNS) diseases. This study presents a covalent functionalization strategy to attach cannabidiol (CBD), the major non-psychotropic phytocannabinoid, to lipid nanocapsules (LNCs) to enhance their BBB permeability in vitro and in vivo. Using click chemistry, two highly monodisperse CBD-functionalized LNC formulations are prepared, LNC1CBD and LNC2CBD, with sizes of 27.0 ± 0.8 nm and 55.0 ± 2.5 nm, and functionalization efficiencies of 30.82 ± 5.93% and 29.59 ± 8.34%, respectively. LNC2CBD exhibits a 55.77% increase in cellular uptake relative to non-functionalized LNCs. In vitro permeability assays demonstrate that LNC1CBD significantly enhances translocation across the healthy BBB at earlier timepoints (4, 8 and 12 h), whereas LNC2CBD exhibits enhanced permeability at later stages (12 and 24 h) compared to their non-functionalized counterparts. This trend is maintained in a diseased BBB model, where CBD functionalization significantly improves permeability at nearly all timepoints for both formulations. Biodistribution studies in healthy mice validate these findings. LNC1CBD significantly increases brain accumulation by 14.87% at 30 min, while LNC2CBD maintains this effect, reaching 17.64% at 30 min, 38.23% at 90 min and 73.53% at 240 min, relative to non-functionalized LNCs. These findings underscore the potential of LNCs covalently functionalized with CBD as a promising platform for CNS-targeted delivery, which can ultimately open new avenues for therapeutic agents that do not usually reach the brain parenchyma at effective concentrations.