BBB opening by low pulsed electric fields, depicted by delayed-contrast MRI, enables efficient delivery of therapeutic doxorubicin doses into mice brains

Fluids and Barriers of the CNS

Research

Orit Furman¹  Leor Zach²  Yael Mardor³  Dianne Daniels⁴  Shirley Sharabi⁴  David Last⁴  Daniel Rand⁵  Orly Ravid⁵  Erez Matsree⁵  Liora Omesi⁵  Chen Shemesh⁵  Sigal Liraz-Zaltsman⁶  Meir Liberman⁷  Itzik Cooper⁸ 

[1] Oncology Institute, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel;School of Medicine, Tel-Aviv University, Tel-Aviv, Israel;Oncology Institute, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel;School of Medicine, Tel-Aviv University, Tel-Aviv, Israel;The Advanced Technology Center, Sheba Medical Center, 52621, Ramat-Gan, Israel;The Advanced Technology Center, Sheba Medical Center, 52621, Ramat-Gan, Israel;The Joseph Sagol Neuroscience Center, Sheba Medical Center, 52621, Ramat-Gan, Israel;The Joseph Sagol Neuroscience Center, Sheba Medical Center, 52621, Ramat-Gan, Israel;Department of Pharmacology, The Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel;Institute for Health and Medical Professions, Department of Sports Therapy, Ono Academic College, Kiryat Ono, Israel;The Joseph Sagol Neuroscience Center, Sheba Medical Center, 52621, Ramat-Gan, Israel;School of Medicine, Tel-Aviv University, Tel-Aviv, Israel;The Joseph Sagol Neuroscience Center, Sheba Medical Center, 52621, Ramat-Gan, Israel;School of Medicine, Tel-Aviv University, Tel-Aviv, Israel;School of Psychology, Reichman University, Herzliya, Israel;

关键词: Blood-brain barrier;    Drug delivery;    MRI;    DCM;    Pulsed electrical fields;    Brain tumor;   

DOI  :  10.1186/s12987-023-00468-7

 received in 2023-07-30, accepted in 2023-09-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPharmacological treatment of CNS diseases is limited due to the presence of the blood-brain barrier (BBB). Recent years showed significant advancement in the field of CNS drug delivery enablers, with technologies such as MR-guided focused ultrasound reaching clinical trials. This have inspired researchers in the field to invent novel brain barriers opening (BBo) technologies that are required to be simple, fast, safe and efficient. One such technology, recently developed by us, is BDF (Barrier Disrupting Fields), based on low pulsed electric fields (L-PEFs) for opening the BBB in a controlled, safe, reversible and non-invasive manner. Here, we conducted an in vivo study to show that BDF is a feasible technology for delivering Doxorubicin (Doxo) into mice brain. Means for depicting BBBo levels were developed and applied for monitoring the treatment and predicting response. Overall, the goals of the presented study were to demonstrate the feasibility for delivering therapeutic Doxo doses into naïve and tumor-bearing mice brains and applying delayed–contrast MRI (DCM) for monitoring the levels of BBBo.MethodsL-PEFs were applied using plate electrodes placed on the intact skull of naïve mice. L-PEFs/Sham mice were scanned immediately after the procedure by DCM (“MRI experiment”), or injected with Doxo and Trypan blue followed by delayed (4 h) perfusion and brain extraction (“Doxo experiment”). Doxo concentrations were measured in brain samples using confocal microscopy and compared to IC50 of Doxo in glioma cell lines in vitro. In order to map BBBo extent throughout the brain, pixel by pixel MR image analysis was performed using the DCM data. Finally, the efficacy of L-PEFs in combination with Doxo was tested in nude mice bearing intracranial human glioma tumors.ResultsSignificant amount of Doxo was found in cortical regions of all L-PEFs-treated mice brains (0.50 ± 0.06 µg Doxo/gr brain) while in Sham brains, Doxo concentrations were below or on the verge of detection limit (0.03 ± 0.02 µg Doxo/gr brain). This concentration was x97 higher than IC50 of Doxo calculated in gl261 mouse glioma cells and x8 higher than IC50 of Doxo calculated in U87 human glioma cells. DCM analysis revealed significant BBBo levels in the cortical regions of L-PEFs-treated mice; the average volume of BBBo in the L-PEFs-treated mice was x29 higher than in the Sham group. The calculated BBBo levels dropped exponentially as a function of BBBo threshold, similarly to the electric fields distribution in the brain. Finally, combining non-invasive L-PEFs with Doxo significantly decreased brain tumors growth rates in nude mice.ConclusionsOur results demonstrate significant BBBo levels induced by extra-cranial L-PEFs, enabling efficient delivery of therapeutic Doxo doses into the brain and reducing tumor growth. As BBBo was undetectable by standard contrast-enhanced MRI, DCM was applied to generate maps depicting the BBBo levels throughout the brain. These findings suggest that BDF is a promising technology for efficient drug delivery into the brain with important implications for future treatment of brain cancer and additional CNS diseases.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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