Right Treatment Wrong Time: Immunotherapy Administration Post-Radiotherapy Decreases Tumor Burden in a Preclinical Model of Brain Metastasis

This dissertation (a) provided an in-depth literature review of methods to modulate the blood-brain and blood-tumor barriers to increase drug delivery and efficacy in brain metastases, (b) evaluated the effects of whole-brain radiation therapy on the blood-brain barrier in immunocompetent and immunocompromised mouse models and proposed a mechanism by which the immune response to radiation disrupts the blood-brain barrier, and (c) developed a syngeneic lung cancer brain metastasis model to determine the impact of coordinated immunotherapy administration with radiotherapy. The blood-brain barrier is an impediment to drug delivery to the brain. The inherent leakiness of the blood-tumor barrier does not allow cytotoxic concentrations of drugs to accumulate within the tumor bed. Methods to modulate the barrier are necessary to increase delivery and efficacy of therapeutics. Whole-brain radiation therapy increases blood-brain barrier permeability in a time- and size-dependent manner in immunocompetent, but not immunocompromised mice. Our findings indicate a window of time that may allow greater drug accumulation post-radiotherapy. Combining immunotherapy and radiotherapy has a synergistic effect. Our data demonstrate the impact immune response and treatment sequencing have on brain tumor burden

A Review of Mathematics Determining Solute Uptake at the Blood–Brain Barrier in Normal and Pathological Conditions

The blood–brain barrier (BBB) limits movement of solutes from the lumen of the brain microvascular capillary system into the parenchyma. The unidirectional transfer constant, Kin, is the rate at which transport across the BBB occurs for individual molecules. Single and multiple uptake experiments are available for the determination of Kin for new drug candidates using both intravenous and in situ protocols. Additionally, the single uptake method can be used to determine Kin in heterogeneous pathophysiological conditions such as stroke, brain cancers, and Alzheimer’s disease. In this review, we briefly cover the anatomy and physiology of the BBB, discuss the impact of efflux transporters on solute uptake, and provide an overview of the single-timepoint method for determination of Kin values. Lastly, we compare preclinical Kin experimental results with human parallels