DDEL-18EVIDENCE THE TRANSPORTER PEPTIDE, K16ApoE, TRANSIENTLY OPENS THE BLOOD-BRAIN BARRIER TO ALLOW PASSAGE OF MOLECULES TO THE BRAIN

Abstract

BACKGROUND: Novel avenues for delivering drugs to the brain are needed for the treatment of patients with brain cancer. We have created a carrier peptide, K16ApoE, which is modeled along apolipoprotein E-low density lipoprotein receptor (ApoE-LDLR) interactions that allows passage of both large and small molecules across the blood-brain barrier (BBB). The mechanism underlying K16ApoE-mediated brain targeting of molecules remains to be established. We provide evidence that K16ApoE creates transient opening of the BBB allowing passage of molecules to the brain. METHODS: Trans-endothelial electrical resistance (TEER) and sucrose permeability were determined using an in vitro BBB model consisted of endothelial cells for the ‘lumen’ side and astrocytes on the ‘brain’ side. Brain delivery of Evans Blue and cisplatin was achieved by administration of K16ApoE followed by injection of the compounds through the femoral vein. Brain uptake of cisplatin was quantified by atomic absorption spectrometry. RESULTS: Control in vitro BBB model (no K16ApoE) showed high TEER and a sucrose impermeable ‘brain’ side, indicating intact ‘barrier’. However, the presence of K16ApoE produced rapid and reversible decrease (∼3-fold) as well as an increase in sucrose permeability, suggesting transient opening of endothelial tight junctions. This observation was then evaluated further by delivering Evans Blue and cisplatin with and without K16ApoE. No Evans Blue brain uptake occurred when the dye was injected alone. However, mice brains were visibly blue when the dye was injected after injection of K16ApoE. Brain uptake of cisplatin was ∼40-fold greater with K16ApoE than without, amounting to brain uptake of ∼1.5% of the injected dose of cisplatin. SIGNIFICANCE: The results suggest K16ApoE renders the BBB transiently permeable, which may be utilized for brain targeting of chemotherapy drugs. Thus, the method may offer a simple avenue for pre-clinical evaluation of drugs against brain cancer and potentially other neurological disorders.