Triculture Model of In Vitro BBB and its Application to Study BBB-Associated Chemosensitivity and Drug Delivery in Glioblastoma

Abstract

Physiologically, brain tumors interact with surrounding vascular and glial cells, and change their responses to survive in brain tissue-specific microenvironments. A major difficulty in brain tumor treatment is caused by the organism's high resistance to pharmaceutical drugs and poor blood-brain barrier (BBB) penetration. Therefore, mimicking the physiological environment of brain tumors on in vitro platforms can aid in predicting the cellular response to drugs. Here, an engineered 3D human glioblastoma in vitro platform that is integrated with a tricultured BBB is presented. First, the barrier function of the constructed BBB model and its reversibility are characterized, after administrating BBB-opening agents through the microvasculature. The brain tumor cells that are cocultured in the BBB show a more aggressive growth pattern and high drug resistance, as well as secreting high concentrations of inflammatory cytokines. Finally, the delivery of BBB-nonpenetrating drugs are promoted by chemically opening the BBB. The results of this study indicate that the platform can potentially study the physiology of the BBB, and monitor drug responses based on the interaction of the brain tumor and BBB.