LASER INTERSTITIAL THERMAL THERAPY INCREASES BLOOD-BRAIN BARRIER AND BLOOD-TUMOR BARRIER PERMEABILITY IN A MOUSE MODEL OF GLIOBLASTOMA

Abstract INTRODUCTION A central challenge in glioblastoma treatment is the presence of the blood-brain barrier (BBB) and blood-tumor barrier (BTB), which prevent access of drugs to the brain and tumor respectively. Recent evidence in patients suggests laser interstitial thermal therapy (LITT), used clinically for tumor ablation, locally disrupts BBB integrity, potentially creating a therapeutic window to deliver otherwise brain-impermeant agents. METHODS A mouse model for LITT, established using a Nd-YAG laser coupled to a 600 mm fiber optic and thermocouple probe, was inserted via burrhole to target the somatosensory cortex. Syngeneic GL261 tumor cells were stereotactically implanted prior to LITT. BBB and BTB permeability were assessed through measurement of fluorescein and doxorubicin after IV injection. Permeability of IV dextran (10 and 70 kDa) and human IgG was monitored by immunohistochemistry (IHC) analysis. Mechanisms of BBB breakdown in vivo were explored utilizing electron microscopy and IHC. RESULTS By fluorescein assay, LITT-induced BBB and BTB permeability began one day post-treatment and was sustained for at least 2 weeks. Additionally, both normal brain and brain tumors demonstrated an increase in Dextran 10 kDa, Dextran 70 kDa, and human IgG extravasation after IV injection in vivo. Mechanistically, we provide evidence that LITT triggers both a decrease in tight junction integrity and an increase in brain endothelial cell transcytosis. As proof-of-concept that LITT can enhance tumor delivery of systemic drugs, LITT increased IV doxorubicin permeability in brain in vivo. Moreover, LITT plus doxorubicin significantly increased survival in brain tumor-bearing mice compared to doxorubicin or LITT alone. CONCLUSIONS Our data suggest that LITT increases BBB and BTB permeability over a defined time window to large molecular weight agents, including antibodies, through multiple cellular mechanisms. Our preclinical results with LITT plus doxorubicin, which mirror a current clinical trial, indicate LITT can enhance the efficacy of systemically delivered drugs.