Distribution and efficacy of chemotherapeutics in the treatment of preclinical brain metastases of breast cancer

Brain metastases are a critical, life-threatening problem for women with advanced metastatic breast cancer. Approximately 80% of women with disseminated central lesions are unable to survive the first year after diagnosis. Despite the breakdown of the blood-brain barrier, chemotherapeutics have limited penetration and distribution into brain metastases and are unable to induce cytotoxicity in the tumor. Limiting the development of new treatments for brain metastases of breast cancer, there are no commercially available in vitro models available that accurately model, and mimic the functionality of, the in vivo blood-tumor barrier (BTB). In an attempt to address the aforementioned problem, the following connected, but independent aims were proposed and completed in a novel microfluidic device: (1) Determine the permeability of three passive markers and one subject to efflux, in blood-brain barrier (BBB) and BTB models (2) Determine if trastuzumab crosses the BBB and BTB barrier in both in vivo and in vitro models (3) Evaluate if the microfluidic BBB and BTB models are relevant and comparable to current in vivo models. Further, based on the data presented herein, additional questions and trials have evolved into an evolution of the current microfluidic chip, discussed in the final chapter. This dissertation incorporates multiple innovative and complex experiments, which suggest that the current microfluidic chip accurately portrays the BBB and BTB when compared to the in vivo barriers, and is a readily available and rapid throughput model for all cancer, as well as BBB, researchers