Anales RANF

Nannocannabinoids for brain tumor drug delivery @Real Academia Nacional de Farmacia. Spain 207 efficiency (which is not the case for the transport ratio expressed as percentage of passage across the endothelial monolayer). Results from the permeability experiments were consistent with those obtained with uptake studies. The BBB permeability coefficients were significantly higher for smaller LNCs (2.8-fold for undecorated LNCs, p < 0.01 and 2.5-fold for CBD-adsorbed LNCs, p< 0.001). As particle size determined the permeability coefficient, the influence of CBD adsorption was then assessed from a comparison of equally-sized LNCs. The adsorption of CBD on LNCs enhanced by 5.2-fold (p < 0.001) the permeability coefficient of their undecorated equally-sized counterparts. Figure 5: Quantitative analysis of influence of particle size reduction and functionalization with CBD on the permeability coefficient of LNCs of LNCs across the hCMEC/D3 monolayer. *: p<0.05, **: p<0.01, ***: p<0.001. These results have been validated with biodistribution studies. Although pathophysiological models have often been used to evaluate the brain targeting efficiency, given that BBB disruption only occurs in the most damaged brain areas, we aimed at evidencing targeting properties at earlier stages of the brain diseases with biodistribution studies in healthy mice. As the size distribution features of DiD-labeled LNCs were analogous to their DiO-labeled counterparts (Figure 2), the same comparisons as those drawn in vitro have been made in vivo . We have determined the percentage of the injected dose per gram of organ in brain (Figure 6), blood, lungs, kidneys, heart, spleen and liver (Figure S2). The in vivo results confirmed the results obtained with the in vitro BBB model: a decrease in particle size yielded a higher transcytosis rate to brain (1.6-fold for undecorated LNCs, p < 0.05 and 2.2-fold for CBD-adsorbed LNCs, p < 0.01). Given the influence of particle size on the brain distribution, the influence of CBD adsorption was then assessed from a comparison of equally-sized LNCs. The functionalization of LNCs with CBD enhanced by 2.4-fold (p < 0.01) the in vivo brain targeting of their undecorated equally-sized counterparts. The increase in brain levels highly correlated with higher available plasma concentration and, in most cases, with lower recognition by the reticuloendothelial organs (Figure S2). Remarkably, the enhancement in brain targeting achieved with the adsorption of CBD on LNCs outperformed by 6-fold that of the gluthatione functionalization strategy assessed in a seminal study with healthy mice that laid the foundations for the G- Technology ® (the main brain active strategy that has already entered clinical trials for the treatment of brain diseases) (54). The brain targeting ability of CBD- decorated LNCs is likely mediated by receptor-mediated transcytosis across the brain endothelium (55). Among the many receptors located at the CNS level to which CBD binds, dopamine receptor has been reported to specifically locate at the BBB and has recently started being tested as a potential receptor to mediate brain targeting of nanocarriers with exogenous ligands (56).