A perfused, parallelized blood brain barrier-tumor platform for compound permeation and efficacy investigations

Few therapeutic options for treating neurological diseases are currently available due to the extremely selective nature of the blood-brain barrier (BBB), which strongly limits drug delivery from the systemic circulation into the central nervous system. The lack of effective treatment options is particularly dire for brain tumors, which ultimately result in very low survival rates. To address the challenge of evaluating drug permeation and efficacy within a physiologically relevant context, we developed a perfused, open-microfluidic platform that includes a human BBB model in co-culture with tumor spheroids. The platform was fabricated from inert plastics to enable quantitative small molecule testing, and it featured 32 testing units in a well-plate format. A pump-free, gravity-driven flow scheme was adopted to establish physiological shear-stress conditions and to enable simple parallelization on tilting stages for increased throughput. We tested the efficacy and permeation of four FDA-approved small-molecule chemotherapeutics - cisplatin, doxorubicin, homoharringtonine, and docetaxel on two patient-derived diffuse-midline-glioma models at sub-IC₅₀ drug concentrations for the BBB. Our results demonstrate that the in vitro BBB significantly limited drug delivery to the tumor, thereby limiting drug efficacy. Furthermore, drug-induced BBB disruption occurred at sub-toxic doses, which led to increased drug permeation to the glioma models. Finally, cell-model-specific responses revealed distinct cytotoxicity behavior, demonstrating the importance of personalized therapy testing. Our scalable BBB-tumor platform provides a physiologically relevant in vitro model system to assess drug permeation, cytotoxicity, and tumor-BBB interactions and offers the potential to advance the discovery of new effective therapeutics against neurological diseases.