Research Assistant Ankara University Ankara University, Department of Biomedical Engineering, Ankara, Turkey
Abstract: The primary barrier restricting access to the central nervous system (CNS) is the blood-brain barrier (BBB). Its properties differ in the presence of neurological diseases. This restriction and diversity of features remain a significant challenge in most CNS-related studies investigating nanoparticle (NP) delivery to the brain for a particular purpose, like glioblastoma multiforme (GBM) therapy. For these studies, maintaining BBB’s integrity and studying its characterization is crucial at first glance. Although decades have been devoted to better understanding and mimicking BBB via several in vitro BBB models, the variability of BBB data and the lack of personalized in vitro BBB modeling for NP transport have been presented. Herein, our study approach is to exploit human induced pluripotent stem cells (hiPSCs) to create a perfect human BBB modeling in vitro. In our study, hiPSCs were transduced from peripheral blood mononuclear cells of one healthy human and successfully differentiated into brain microvascular endothelial cells (BMECs). More importantly, for the first time, a relatively novel NP, titanium carbide/oxide (Ti3C2Tx) MXene quantum dots (MQDs), was tested for its delivery across the hiPSCs-derived BBB model and its uptake by brain tumors needed for treating GBM. Our experimental results found that the hiPSCs-derived model resembled in vivo BBB more than the model with hCMEC/D3 cell lines, and it expressed several BBB genes essential for the brain endothelium. Accordingly, 10-fold higher occludin gene expression in the model with hiPSCs-derived BMECs than that of immortalized BMEC lines was found, indicating better BBB integrity. Moreover, in our transport-related studies, Ti3C2Tx MQDs were tracked by their auto-fluorescence, and the percentage of fluorescence by tumor cells in our MQD-treated model was 2-fold higher than in the untreated model, showing MQD transport across the BBB, and detection inside the brain tumor cells. Therefore, our study demonstrates the creation of well-developed BMECs, forming a protective membrane with the help of hiPSCs. It also emphasizes important points researchers consider in the BBB modeling for in vitro studies in neuro-nanotechnology. Finally, it offers a pivotal in vitro BBB model for personalized GBM therapy with MQDs and guides future studies in vivo.
Funding Source: Tubitak 1004, Regenerative and Restorative Medicine Research and Applications, 20AG003-P8. Project, Obtaining a human induced pluripotent stem cell-based blood brain barrier model, TSG-2024-3419.
