INTRODUCTION: The role of the blood-brain barrier in therapeutic failure of brain metastases has remained unanswered for many years. Blood vessels within the brain are uniquely characterized by low passive permeability and active efflux transport which limits brain penetration for many agents. In this presentation, we address this issue using novel imaging methods to simultaneously assess brain metastasis vascular permeability, chemotherapeutic drug uptake, and drug efficacy in preclinical models of breast cancer.METHODS: Brain-seeking breast carcinoma cells were injected into the left cardiac ventricle of immune-compromised mice. Tumors were allowed to seed and grow within the central nervous system for 2-6 weeks. Mice were then anesthetized and administered radiolabeled chemotherapeutic drug (0.5 � 8 hr) as well as a vascular permeability marker. At the end of the circulation period, brain was removed from the skull, snap frozen, and cut into sections for fluorescence/phosphorescence permeability, drug distribution, and immunohistochemical analyses.RESULTS: Barrier passive permeability was elevated 2-30 fold in most brain metastases relative to surrounding brain. Chemotherapeutic drug (e.g. paclitaxel, doxorubicin, vinorelbine, lapatinib, capecitabine, vorinostat) uptake was also heterogeneously enhanced in most (85%) brain metastases. However, drug concentrations in brain metastases were, on average, only 2-15% of those in metastases in other tissues (e.g., liver, kidney) that lack a tight vascular barrier. Apoptosis was observed only in the subset (~10%) of the most highly permeable brain metastases where drug concentration approached that of systemic lesions. Enhanced brain metastasis uptake for paclitaxel and doxorubicin correlated with elevated barrier passive permeability but not with altered active efflux transport. Uptake could be enhanced up to 100-fold through inhibition of active efflux transport. The results demonstrate that the brain metastasis barrier, though partially compromised, still markedly limits drug delivery for many chemotherapeutic agents.

Drug delivery to brain tumors and the problem of the blood-brain barrier

247th National Meeting (2014)

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