Gene Delivery to the Blood-Brain Barrier

Drug- and gene delivery to the brain is highly restricted by the vascular barriers of the brain, denoted by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barriers. Among these barriers, BBB is the main limiting factor. It is composed by the brain capillary endothelial cells (BCECs). The BCECs barrier function is supported by astrocytes, pericytes and neurons to form the blood-brain barrier. BCECs are very tightly connected to each other by tight junctions. Apart from the essential substrates needed to nourish the brain, small and/or lipophilic molecules are free to diffuse into the brain. However most pharmacologically active drugs and gene fragments are too large to enter the brain. Various kinds of drug-carriers have been constructed for delivery of large substances to the brain. Such drug-carriers have to be able to successfully carry their cargo through the BCECs and into the brain. For testing the ability of drug-carriers to deliver their cargo into the brain, investigators have constructed different in vitro BBB models, consisting of BCECs that express the main characteristics of the BBB in vivo. In the first part of the thesis the ability of two drug-carriers, pullulanspermine and SPIOs, to mediate transfection of BCECs or transcellular transport through BCECs in vitro was studied.