CNSC-03. EXPLORING STRUCTURAL DISRUPTION OF TRICELLULAR JUNCTIONS TO ENHANCE BLOOD-BRAIN-BARRIER PERMEABILITY

Abstract The blood-brain barrier (BBB) hinders CNS chemotherapy entry for malignant glioma treatment. It is predominantly composed of brain endothelium linked by bicellular (BJ) and tricellular (TJ) tight junctions. Previous studies demonstrated,angubindin-1 inhibited TJ angulin-1 to increase CSF targeted therapy in rodent lung cancer models. We hypothesize angubindin-1 can transiently decrease BBB junctional integrity permeability prolong model survival. Rat endothelial cells were treated with BJ inhibitors against (angubindin-1 600µg/mL), claudin-3 (C-CPE 200µg/mL) or claudin-5 (C-CPE-MT 200µg/mL). Endothelial was assessed immunoblotting cell-cell electrical impedance. Effects on efflux transporter P-glycoprotein (PGP) migration studied using rat human derived cells. models doxil (3 mg/kg), (10 mg/kg 30 combination assessments tumor volume, observed decreased expression 5 hours after treatment, return baseline 24 (p<0.05). Angubindin-1, CCPE, CCPE-mt globally reduced integrity, maximally at 4 a 12 hours; demonstrating the largest cell-adhesion vs control, p< 0.0001). Angubindin-1 also PGP rhodamine both cells, along pro-migratory dose-dependent effect Combined increased survival compared alone (24 days vs. 18 days, p < Day 14 volume significantly treatment respectively (77.5 % 81.6 %, p<0.05). Ongoing are exploring, angubindin-1’s large drug permeability, localization post disruption additional combinational treatments Collectively, these findings pose unique opportunity disrupt improve options.