Abstract Brain metastases remain exceptionally challenging to treat, in part because many candidate therapies fail to demonstrate the clinical benefit observed in preclinical studies. A major contributor to this gap is the limited ability of traditional animal models to accurately replicate the functional blood–brain barrier (BBB). Conventional intracranial orthotopic tumor models are commonly used but inherently compromise BBB integrity, reducing their utility for evaluating drug penetration and therapeutic performance. Other implantation routes, such as intravenous or intracardiac delivery, better preserve the BBB but often produce extensive extra-cranial metastases, shortening study duration and diminishing relevance for brain-specific disease. To overcome these limitations, we established an intra-carotid tumor cell delivery method that selectively seeds the brain while minimizing systemic spread. This technique enables localized tumor growth in disease relevant brain regions without disrupting BBB architecture. Tumor progression and spatial distribution were followed longitudinally using magnetic resonance imaging (MRI) together with bioluminescence imaging (BLI). These modalities consistently demonstrated reliable brain colonization and supported high-resolution tracking of tumor growth dynamics. Our intra-carotid model provides a more physiologically faithful system for studying metastatic brain disease. By retaining BBB functionality and supporting reproducible, long-term monitoring, this platform offers a powerful tool for assessing BBB-permeant therapeutics and may enhance the translational value of preclinical studies in for brain targeted therapies, particularly in the context of metastatic disease. Citation Format: T. Liz Bailey, Melissa Tran, Cheryl Davis, Ben Hoerner, Victoria Caruso, Kathleen Hutchinson, Helen Ketteringham, Corrine Silvio, Shannan Paul, Chris Holding, Aliccia Koznecki, Dawn Lusk, Shorena Nadaraia-Hoke. Maintaining blood-brain barrier integrity in translational brain tumor models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2171.
Bailey et al. (2026) studied this question.