Author ORCID Identifier

https://orcid.org/0000-0003-4602-9514

Semester

Fall

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Paul Lockman

Committee Member

Marina Galvez-Peralta

Committee Member

Salik Hussain

Committee Member

Ahmad Hanif

Committee Member

Edwin Wan

Abstract

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.

Download

Share

COinS