Anales RANF

Juan Aparicio Blanco, Ignacio A. Romero, Jean P Benoit, Ana I. Torres Suárez @Real Academia Nacional de Farmacia. Spain 200 Table 1: Published articles on the encapsulation of different kinds of cannabinoids within nanocarriers. 9 Δ-THC: 9-delta-tetrahydrocannabinol, AEA: anandamide. Cannabinoid Type of cannabinoid Carrier Therapeutic potential Ref 9 Δ-THC Phytocannabinoid Mesoporous silica nanoparticles In vivo neuropathic pain relief (15) 9 Δ-THC Phytocannabinoid PLGA nanoparticles In vitro and in vivo chemotherapy for lung cancer (16) 9 Δ-THC Phytocannabinoid PLGA nanoparticles In vitro chemotherapy for colon adenocarcinoma (17) 9 Δ-THC and CBD Phytocannabinoid Nanolipospheres - (18) AEA Endocannabinoid Poly-ε-caprolactone nanoparticles - (19) Rimonabant Synthetic cannabidomimetic Nanostructured lipid carriers - (20) Rimonabant, URB597 and AM251 Synthetic cannabidomimetic Nanostructured lipid carriers - (21) WIN55,212-2 Synthetic cannabidomimetic Styrene maleic acid micelles In vivo neuropathic pain relief (22) Dexanabinol Synthetic cannabidomimetic Solid lipid nanoparticles In vivo antidepressant effect (23) CB13 Synthetic cannabidomimetic PLGA nanoparticles In vivo neuropathic pain relief (24) CB13 Synthetic cannabidomimetic PLGA nanoparticles - (25, 26) CB13 Synthetic cannabidomimetic Lipid nanoparticles - (25, 27) To be efficacious following intravenous administration, these carriers must be able to traverse the BBB to ultimately reach the tumor cells. Unfortunately, although the paracellular permeability of the brain endothelium is altered in most brain diseases, this disruption only occurs substantially in advanced stages of disease and in the most affected regions (28, 29) . Therefore, brain targeting should not solely rely on passive targeting. Alternatively, brain active targeting is being explored to boost the transcellular delivery efficiency of nanocarriers across the BBB (30). Brain active targeting is based on the modification of nanocarriers with moieties that trigger receptor-mediated transcytosis into the central nervous system (CNS) through specific binding with transporters overexpressed on the brain endothelium. Although numerous receptors have been used to design brain active targeting strategies across the BBB, the translational impact of brain active targeting remains modest, as only three actively-targeted liposomes have reached the clinical trials stage for distinct brain conditions (ClinicalTrials.gov identifiers: NCT01386580, NCT02048358 and NCT02340156) due to the flaws of the currently available targeting moieties (namely, the development of competitive phenomena with endogenous ligands and/or of immunogenicity) (31, 32). Therefore, research on novel exogenous non- immunogenic moieties is likely to thrive shortly. In this respect, CBD has been reported to bind to various receptors located on the brain endothelium environment: namely, cannabinoid receptors CB 1 (33) and CB 2 (34), serotoninergic receptor 5-HT 1A (35), transient potential vanilloid receptors TRPV 1–2 (36), glycine receptor (37), adenosine receptor A 2A (38), G-protein-coupled receptor 55 GPR55 (39) and dopamine receptor D 2 (40)). Apart from those receptors normally overexpressed on the brain endothelium, those overexpressed on tumor cells can also be used for active targeting of brain tumors to promote the selective distribution to glioma cells. In this respect, the expression of some of the receptors to which the cannabinoids bind has been reported to be increased in glioma (namely, cannabinoid receptors 1 and 2 (CB 1 and CB 2 ) (41), transient potential vanilloid receptor type 2 (TRPV2) (36) and G-protein-coupled receptor 55 (GPR55) (42). Hence, we have designed two distinct strategies to incorporate CBD in the aforesaid size-tailored LNCs for glioma therapy depending on the ultimate therapeutic purpose. On the one hand, we have introduced herein a pioneering functionalization strategy for brain tumor targeting of LNCs with CBD under the assumption that, if existing, this double BBB- and glioma-targeting effect will ultimately enable a dual-targeting strategy for intravenous treatment of glioma to be achieved. The BBB-targeting efficiency of this active targeting strategy has been explored in vitro and in vivo , whereas the glioma-targeting efficiency has been assessed in vitro with the human glioblastoma cell line U373MG. As the mechanisms that drive the distinct active targeting strategies may follow a