The effectiveness of anticancer treatment can be compromised by structural or physiological barriers. This is particularly true for the treatment of intracranial malignancies. The grim prognosis associated with these tumors is due in part to the inability of anticancer agents to penetrate the blood-brain-barrier (BBB) into the tumor microenvironment. Currently, the dominant treatment modality employed to treat both primary and metastatic intracranial tumors is radiation therapy (RT). RT has been reported to increase BBB permeability within intracranial tumors, i.e., at the Tumor Blood-Brain-Barrier (T-BBB). However, modulation of the T-BBB by targeted RT for therapeutic gain has surprisingly not been extensively studied. We therefore propose to systematically characterize RT-induced modulation of the T-BBB utilizing a variety of powerful new magnetic resonance imaging (MRI) modalities. The goal here is to objectively determine optimal conditions for T-BBB disruption using both preclinical and clinical studies of human brain tumors, including implications of timing and radiation dose for improving the targeted delivery of novel therapeutic nanocarriers. This pilot research study therefore proposes to test the hypothesis that radiation-induced modulation of the T-BBB will facilitate the enhanced permeation and retention (EPR) of paclitaxel- loaded nanobiopolymers in brain tumors, resulting in increased efficacy. We seek to develop optimal treatment strategies that integrate with RT the enhanced permeation and retention (EPR) characteristics of nano- cylindrical 'filomicelles'- which can in principle carry enough drug to kill a cancer cell. Incorporating nanocarrier drug delivery with T-BBB modulation by radiation therapy leverages our unique interdisciplinary, interdepartmental, and institutional expertise. Our studies will take advantage of recent advances in MRI and nanobiopolymer delivery technologies in combination with unique cellular and molecular biology tools we have developed.
The ultimate goal of our studies is to translate our findings into future brain tumor clinical trials. This study should develop new paradigms for delivering therapeutic agents into the brain in coordination with radiation to treat intracranial malignancies more effectively, and may have implications for therapy of other neurologic diseases. The long-term goals of this proposal, which are directly relevant to public health are the following: (1) To improve the efficacy of radiation therapy in patients with intracranial malignancies by combining it with nanobiopolymer-delivered therapeutic agents;and (2) To generate data confirming a rational basis for the clinical use of nanobiopolymer- delivered Taxol with radiation therapy to treat both primary and metastatic intracranial tumors. We believe that successful implementation of this research will contribute to the establishment of new strategies for the treatment of intracranial malignancies.
