Combinatorial Treatments and Technologies for Safe and Effective Targeting of Malignant Gliomas Using High-Frequency Irreversible Electroporation.

Glioblastoma Multiforme (GBM) is a highly aggressive and prevalent brain tumor with an average 5-year survival rate of approximately 6.9%. Its complex pathophysiology, characterized by the capacity to invade surrounding tissues beyond the visible tumor margin, intratumor heterogeneity, hypoxic core, and the presence of the blood-brain barrier (BBB) that restricts the penetration of large therapeutic agents, all pose formidable challenges for effective therapeutic intervention. The standard of care for GBM has thus far exhibited limited success, and patients often face a poor prognosis. Electroporation-based therapies, such as irreversible electroporation (IRE), have emerged as promising alternatives to conventional treatments. By utilizing high amplitude pulsed electric fields, IRE is able to permeabilize cells, disrupt the BBB, and induce non thermal ablation of soft tissues. However, IRE is oftentimes accompanied by undesirable secondary effects such as muscle contractions, complex anesthetic protocols, and susceptibility to electrical heterogeneities, which have impeded its clinical translation. To address these limitations, high-frequency IRE (H-FIRE) was developed. H-FIRE employs short bursts of bipolar pulses, similar in duration to the cell charging time constant, enabling the desired tissue ablation while minimizing nerve excitation and muscle contractions. Additionally, H-FIRE reduces susceptibility to electrical heterogeneities, allowing for more predictable treatment volumes, thus enhancing the feasibility of clinical translation. This dissertation investigates H-FIRE for targeting malignant gliomas while looking into improved efficacy when administering the therapy in conjunction with other treatment forms and technologies. Specifically, the presented work focuses on several key areas: (1) determining the effect of pulsing protocol and geometric configuration selection on the biological outcomes from electroporation; (2) using a tumor bearing rodent glioma model to evaluate the effects of H-FIRE as a standalone therapy and as a combinatorial therapy with liposomal doxorubicin; (3) investigating the effects of waveform shape on biological outcomes; (4) utilizing real-time Fourier Analysis SpecTroscopy (FAST) to accurately model rises in temperature during treatment; and (5) modifying real-time FAST methods to determine treatment endpoints for safe and effective ablation volumes.