Enhancing Nanoparticle Drug Delivery to Brain Tumors with Focused Ultrasound

Abstract

Glioblastoma mulitforme (GBM) is regarded as an incurable and universally fatal disease, characterized by its physical inaccessibility to most therapies and ultimately serve as a source for tumor recurrence which leads to the patient's demise. Furthermore, the prognosis for GBM has not improved significantly over the last 20 years. To achieve meaningful advances in the treatment of GBM, novel strategies must be devised to effectively treat these invasive glioma cells, therein halting the progression of the disease. Our laboratory's research centers on a nanoparticle biologic with the ability to selectively kill cancer cells despite uptake into normal healthy cells. This novel biologic therapy is based on plasma‐derived low‐density lipoprotein (LDL) reconstituted with the natural omega‐3 fatty acid, docosahexaenoic acid (DHA) (herein referred to as LDL‐DHA). However, therapeutic delivery to the brain is infamous due to the BBB that regulates the homeostasis of the brain by cell tight junctions with limited passage to certain molecules and nutrients. To bypass the BBB, Focused Ultrasound (FUS) combined with microbubbles are used to mechanically open the BBB to allow transient and targeted delivery of the brain. FUS in combination with LDL-DHA for delivery in normal rat brains showed safety of FUS and no evidence of cytotoxicity, respectively. However, delivery of the LDL particle by FUS to the brain has not been done in a tumor bearing animal model as well as the evaluation of LDL-DHA toxicity, uptake, and mechanisms in normal and malignant brain cell lines. In this dissertation, we focused on the development of a GBM tumor-bearing mouse model, delivery of LDL particles using FUS to the tumor, and assessment of particle cellular uptake and cytotoxicity by LDL-DHA in normal and malignant murine brain cells lines. In the following chapters we discuss accumulation of LDL particles in the surrounding mouse tumor by FUS, assessed mechanisms of particle uptake in normal and malignant brain cells, and showed the selective toxicity of LDL-DHA to GBM cell lines