The Blood-Brain Barrier Cell-Targeted Gene Delivery System to Enhance Nerve Growth Factor Protein Secretion in the Brain.

Abstract

The enhanced permeability efficiencies still remain a big challenge in crossing the blood-brain barrier (BBB). Herein, a BBB-targeting delivery system based on transferrin (Tf)-poly(ethylene glycol) (PEG) PEGylated-cationic liposome was prepared for delivering the protamine labeled nerve growth factor (NGF) gene. The nanoparticle (TLDP) could preferentially accumulate into the BBB by receptor-mediated transcytosis via the Tf receptor present on cerebral endothelial cells. The polyplex showed good encapsulation of the NGF gene as well as triggered corresponding protein release in the BBB. Surface modification of liposomes with PEG imparts a steric barrier to the NPs that decreases their recognition and clearance by the reticuloendothelial system for increasing the circulation time, and cationic liposomes with protamine are indicated with nuclear localization function to improve the efficiency of nucleus localization and gene expression. The polyplex at a DOTAP/DNA ratio of 3 showed an appropriate diameter, desired serum stability, and much higher encapsulation efficiency. The polyplex had no cytotoxicity against cells. The cell uptake of the TLDP was stronger than other groups without transferrin, which suggested that the TLDP could successfully deliver the NGF gene to the BBB cell and enhanced the expression and secretion of the NGF protein in the brain. In vivo imaging further verified that the TLDP exhibited a higher brain distribution than other groups. Consequently, these findings showed that BBB cells as the "transit station" is a promising method to overcome the BBB and increase the concentration of drug in the brain.