Optimizing Drug Delivery to the Brain for Breast Metastasis: A Novel Method for Tumor Targeting

Abstract

Introduction: Brain metastases are difficult to treat due to the blood-brain barrier limiting the delivery of therapeutic agents to the brain effectively. Intraventricular drug delivery has not been well studied for intraaxial pathologies. However, our prior work demonstrated that intraventricular drug delivery in a hyperosmolar vehicle showed preferential accumulation of drug within breast cancer tissue compared to surrounding brain parenchyma. The focus of this study was to explore the molecular parameters of intraventricular drug administration that may optimize drug delivery to intra-axial brain metastases. Our hypothesis was that a low molecular weight drug with a high osmolarity solution would increase drug delivery to tumor tissue.Methods: We used an intracerebral breast cancer tumor model in adult female nude rats divided into six experimental groups. We examined three iron-labeled dextran molecules (3 kD, 5 kD, and 10 kD) in 337 mOsm/L solution and three different osmolarities of delivery solution (307, 353, and 368 mOsm/L) with 10 kD dextran. 7T magnetic resonance imaging (MRI) was used to analyze dextran distribution at different time points. All animals were sacrificed after two hours, and the quantity of dextran particles was determined by histopathology.Results: Breast cancer tumor cells were successfully implanted in all rats. The MRI quantification of dextran concentration was well corroborated by histopathology. Varying the molecular size of dextran resulted in the smallest molecule reaching peak levels in tumor tissue earlier than the larger molecules, but the larger molecules remained concentrated in tumor tissue for a longer time. Varying the osmolarity of the delivery solution resulted in the preferential accumulation of 10 kD dextran in tumor tissue except for when dextran was delivered in 368 mOsm/L solution where no preferential distribution was seen.Conclusion: Hyperosmolar intraventricular delivery of chemotherapeutic drugs could be effective in preferentially delivering drugs to abnormal tumor tissues.