Neuro-Oncology Advances 2(1), 1–12, 2020 | doi:10.1093/noajnl/vdaa071 | Advance Access date 5 June 2020 1 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. Afshin Salehi † , Mounica R. Paturu † , Bhuvic Patel †, , Matthew D. Cain, Tatenda Mahlokozera, Alicia B. Yang, Tsen-Hsuan Lin, Eric C. Leuthardt, Hiroko Yano, Sheng-Kwei Song, Robyn S. Klein, Robert Schmidt, and Albert H. Kim Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA (A.S., M.R.P., B.P., T.M., A.B.Y., E.C.L., H.Y., A.H.K.); Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA (M.D.C., R.S.K.); Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA (T.H.L., S.K.S.); Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA (H.Y., A.H.K.); Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA (H.Y., A.H.K.); Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA (R.S.K.); Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA (R.S.K., R.S.) † These authors contributed equally to this work. Corresponding Author: Albert H. Kim, MD, PhD, Washington University School of Medicine, 660 S. Euclid Ave, Box 8057, St. Louis, MO 63110, USA (alberthkim@wustl.edu). Abstract Background. The blood–brain and blood–tumor barriers (BBB and BTB), which restrict the entry of most drugs into the brain and tumor, respectively, are a signifcant challenge in the treatment of glioblastoma. Laser inter- stitial thermal therapy (LITT) is a minimally invasive surgical technique increasingly used clinically for tumor cell ablation. Recent evidence suggests that LITT might locally disrupt BBB integrity, creating a potential therapeutic window of opportunity to deliver otherwise brain-impermeant agents. Methods. We established a LITT mouse model to test if laser therapy can increase BBB/BTB permeability in vivo. Mice underwent orthotopic glioblastoma tumor implantation followed by LITT in combination with BBB tracers or the anticancer drug doxorubicin. BBB/BTB permeability was measured using fuorimetry, microscopy, and immu- nofuorescence. An in vitro endothelial cell model was also used to corroborate fndings. Results. LITT substantially disrupted the BBB and BTB locally, with increased permeability up to 30 days after the intervention. Remarkably, molecules as large as human immunoglobulin extravasated through blood vessels and permeated laser-treated brain tissue and tumors. Mechanistically, LITT decreased tight junction integrity and in- creased brain endothelial cell transcytosis. Treatment of mice bearing glioblastoma tumors with LITT and adjuvant doxorubicin, which is typically brain-impermeant, signifcantly increased animal survival. Conclusions. Together, these results suggest that LITT can locally disrupt the BBB and BTB, enabling the targeted delivery of systemic therapies, including, potentially, antibody-based agents. Key Points • Laser therapy increases BBB and BTB permeability up to 30 days posttreatment and enables brain entry of large-molecular-weight moieties. • Laser therapy increases BBB and BTB permeability by disrupting endothelial cell tight junctions and increasing transcytosis. • In a preclinical mouse model, laser ablation with adjuvant chemotherapy signifcantly improved animal survival. Therapeutic enhancement of blood–brain and blood–tumor barriers permeability by laser interstitial thermal therapy Downloaded from https://academic.oup.com/noa/article/2/1/vdaa071/5851923 by guest on 24 September 2021