Date of Graduation

2017

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Paul R Lockman

Committee Co-Chair

Erik A Bey

Committee Member

Yon Rojanasakul

Committee Member

Michael D Schaller

Committee Member

James W Simpkins

Abstract

About 20-40% of advanced breast cancer patients will develop symptomatic brain metastases. Once the patients diagnosed with metastatic brain tumors, there is 80% mortality rate within one year. The presence of blood-brain barrier makes it difficult for drugs to reach the site of action in brain-related ailments. To overcome we came up with two strategies: First, we encapsulated the chemotherapy in a liposome and thereby significantly improving the plasma pharmacokinetics of chemotherapy. We also observed that tumor drug exposure significantly improved by liposomal formulation. This improvement in plasma drug pharmacokinetics and tumor drug accumulation after administration of the liposomal formulation decreased the tumor burden and significantly increased the median survival by 40% when compared to vehicle group in an experimental model of brain metastases. In another strategy, we want to modulate blood-brain barrier in brain metastases to increase permeation. Notch-4 signaling pathway plays an important role in angiogenesis and inhibition of Notch-4 by DAPT will increase the expression of vascular endothelial growth factor receptor-2 ultimately leading to leaky vasculature in metastatic brain tumor. In our studies, we found that inhibition of Notch-4 by DAPT increased the permeation 14C- Aminoisobutyric acid specifically in the brain metastases. We also observed that the progression of tumor burden was decreased when animals were administered both Notch-4 inhibitor and chemotherapy. We also found that median survival is increased by 20% in animals treated with chemotherapy with concurrent Notch-4 inhibition by DAPT. Finally, we evaluated the effect of chemotherapy on normal brain region adjacent to brain metastases. We found that the permeation of fluorescent tracers and 14C-paclitaxel increased in brain adjacent to the tumor. We also found that the expression of activated astrocytes increased in brain adjacent to tumors after chronic chemotherapy treatment in our brain metastases model. Together these results suggest that novel strategies improved survival in brain metastases of breast cancer. Future studies should aim at combining these individual strategies to further increase survival in a preclinical model. At the same time care should be taken not increase chemotherapy permeation into the normal brain as it may lead to unwanted effects like chemo-fog.

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