In vitro models of the interplay between glioblastoma and blood–brain barrier for stratifying drug efficacy

Glioblastoma (GBM) is the most lethal brain cancer in adults, with a dismal prognosis and no curative therapies available. The treatment landscape remains largely stagnant, relying on tumor resection, temozolomide (TMZ) chemotherapy, and radiotherapy, which are hampered by the blood-brain barrier (BBB) that limits drug blood-to-brain permeability and, consequently, therapeutic efficacy. Over 98 % of potential therapeutic candidates fail to penetrate the BBB, significantly contributing to the high recurrence rates of GBM. The urgent need for improved drug delivery strategies is compounded by the limitations of current preclinical models, which often inadequately mimic the complex BBB-GBM interaction. This review discusses recent advancements in the development of in vitro models that accurately replicate the BBB and GBM interplay, ranging from simplified two-dimensional (2D) systems to sophisticated three-dimensional (3D) constructs. Innovations such as microfluidic devices and multicellular spheroid cultures are highlighted as promising methods to enhance physiological relevance and predictive value in drug testing. By emphasizing the interplay between GBM and its microenvironment with the BBB, these models aim to accelerate the discovery and efficacy testing of novel anti-GBM agents. Ultimately, this review underscores the critical need for more representative in vitro platforms that not only reduce reliance on animal models but also adhere to the principles of the 3Rs (replacement, reduction, refinement) in biomedical research, paving the way for more effective therapeutic interventions against GBM.