NS-14A PILOT STUDY OF USING MRI-GUIDED LASER HEAT ABLATION TO INDUCE DISRUPTION OF THE PERITUMORAL BLOOD BRAIN BARRIER TO ENHANCE DELIVERY AND EFFICACY OF TREATMENT OF PEDIATRIC BRAIN TUMORS

Abstract OBJECTIVE In neuro-oncology, it is believed that one major obstacle to effective chemotherapy is the high vascularity and heterogenous permeability of brain tumors. Focused ultrasound (FUS) exposure with the microbubbles has been shown to transiently open the blood-brain barrier (BBB) without depositing thermal energy, and thus may enhance the delivery of various therapeutic drugs into brain tumors. The aim of this study was to evaluate the BBB opening using 220-kHz transcranial MRI-guided FUS (TcMRgFUS) device and microbubbles in mouse and rat. METHODS The experiments were performed with the 220-kHz ExAblate Neuro TcMRgFUS system (InSightec) and novel lipid bubbles (LB, Teikyo Univ.). Normal mouse and rat brains were irradiated with TcMRgFUS (output power, 5W; duration of irradiation, 30 s; duty cycle 100%) following intravenous injection of 6x107 LB per mouse and rat, respectively. On irradiation, target temperature rise & cavitation signal were monitored by MR thermometry and cavitation receiver, respectively. Immediately after irradiation, BBB opening and complications were detected based on T1, T2, T2*, and Gadolinium (Gd) enhanced T1-weighted images. RESULTS The maximum temperature of brain tissue was under 42 C. There were no risky-cavitation signals causing hemorrhage. The FUS-LB exposure induced successful BBB opening effect in both mouse and rat, confirmed by Gd enhancement in the target region, lateral ventricles, and sulcus. In addition, there were no complications such as edema, coagulation, and hemorrhage. CONCLUSIONS Although there remain many conditions to be optimized, BBB opening using a 220-kHz TcMRgFUS device and LB can offer a non-invasive and feasible drug delivery for brain malignancies.

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Nanoparticles for Diagnosis and Target Therapy in Pediatric Brain Cancers

Diagnostics ◽

10.3390/diagnostics12010173 ◽

2022 ◽

Vol 12 (1) ◽

pp. 173

Author(s):

Clara Guido ◽

Clara Baldari ◽

Gabriele Maiorano ◽

Angela Mastronuzzi ◽

Andrea Carai ◽

...

Keyword(s):

Blood Brain Barrier ◽

Standard Treatment ◽

Target Therapy ◽

Tumor Resection ◽

Pediatric Brain Tumors ◽

Brain Barrier ◽

Diagnostic Tools ◽

Blood Brain ◽

Cognitive Problems ◽

Pediatric Brain

Pediatric brain tumors represent the most common types of childhood cancer and novel diagnostic and therapeutic solutions are urgently needed. The gold standard treatment option for brain cancers in children, as in adults, is tumor resection followed by radio- and chemotherapy, but with discouraging therapeutic results. In particular, the last two treatments are often associated to significant neurotoxicity in the developing brain of a child, with resulting disabilities such as cognitive problems, neuroendocrine, and neurosensory dysfunctions/deficits. Nanoparticles have been increasingly and thoroughly investigated as they show great promises as diagnostic tools and vectors for gene/drug therapy for pediatric brain cancer due to their ability to cross the blood–brain barrier. In this review we will discuss the developments of nanoparticle-based strategies as novel precision nanomedicine tools for diagnosis and therapy in pediatric brain cancers, with a particular focus on targeting strategies to overcome the main physiological obstacles that are represented by blood–brain barrier.

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P04.91 ABC-drug efflux transporters at the blood-brain barrier limit the efficacy of treatment against primary and secondary brain tumors

Neuro-Oncology ◽

10.1093/neuonc/noy139.325 ◽

2018 ◽

Vol 20 (suppl_3) ◽

pp. iii301-iii302

Author(s):

O van Tellingen ◽

M C de Gooijer ◽

L C M Buil ◽

L Fan ◽

N A de Vries ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Efflux Transporters ◽

Drug Efflux ◽

Blood Brain ◽

Efficacy Of Treatment ◽

Drug Efflux Transporters

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Blood-brain barrier disruption with low-intensity pulsed ultrasound for the treatment of pediatric brain tumors: a review and perspectives

Neurosurgical FOCUS ◽

10.3171/2019.10.focus19726 ◽

2020 ◽

Vol 48 (1) ◽

pp. E10 ◽

Cited By ~ 3

Author(s):

Kévin Beccaria ◽

Michael Canney ◽

Guillaume Bouchoux ◽

Stéphanie Puget ◽

Jacques Grill ◽

...

Keyword(s):

Drug Delivery ◽

Clinical Trials ◽

Brain Tumors ◽

Blood Brain Barrier ◽

Pediatric Brain Tumors ◽

Brain Barrier ◽

Pulsed Ultrasound ◽

Low Intensity Pulsed Ultrasound ◽

Low Intensity ◽

Pediatric Brain

Pediatric brain tumors are the most common solid tumor and the first cause of cancer death in childhood, adolescence, and young adulthood. Current treatments are far from optimal in most of these tumors and the prognosis remains dismal for many of them. One of the main causes of the failure of current medical treatments is in part due to the existence of the blood-brain barrier (BBB), which limits drug delivery to tumors. Opening of the BBB with low-intensity pulsed ultrasound (LIPU) has emerged during the last 2 decades as a promising technique for enhancing drug delivery to the brain. In preclinical models, enhanced delivery of a wide range of therapeutic agents, from low-molecular-weight drugs, to antibodies and immune cells, has been observed as well as tumor control and increased survival. This technique has recently entered clinical trials with extracranial and intracranial devices. The safety and feasibility of this technique has furthermore been shown in patients treated monthly for recurrent glioblastoma receiving carboplatin chemotherapy. In this review, the characteristics of the BBB in the most common pediatric brain tumors are reviewed. Then, principles and mechanisms of BBB disruption with ultrasound (US) are summarized and described at the histological and biological levels. Lastly, preclinical studies that have used US-induced BBB opening in tumor models, recent clinical trials, and the potential use of this technology in pediatrics are provided.

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Recent advances in nano delivery systems for blood-brain barrier (BBB) penetration and targeting of brain tumors

Drug Discovery Today ◽

10.1016/j.drudis.2021.04.008 ◽

2021 ◽

Author(s):

Shriya Reddy ◽

Katyayani Tatiparti ◽

Samaresh Sau ◽

Arun K. Iyer

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Delivery Systems ◽

Brain Barrier ◽

Blood Brain ◽

Recent Advances

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Treatment with the NK1 Antagonist Emend Reduces Blood Brain Barrier Dysfunction and Edema Formation in an Experimental Model of Brain Tumors

PLoS ONE ◽

10.1371/journal.pone.0097002 ◽

2014 ◽

Vol 9 (5) ◽

pp. e97002 ◽

Cited By ~ 13

Author(s):

Elizabeth Harford-Wright ◽

Kate M. Lewis ◽

Mounir N. Ghabriel ◽

Robert Vink

Keyword(s):

Brain Tumors ◽

Experimental Model ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Edema Formation ◽

Blood Brain ◽

Nk1 Antagonist

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Hyperosmolar blood-brain barrier disruption in baboons: an in vivo study using positron emission tomography and rubidium-82

Journal of Neurosurgery ◽

10.3171/jns.1996.84.3.0494 ◽

1996 ◽

Vol 84 (3) ◽

pp. 494-502 ◽

Cited By ~ 21

Author(s):

Bernhard Zünkeler ◽

Richard E. Carson ◽

Jeffrey Olson ◽

Ronald G. Blasberg ◽

Mary Girton ◽

...

Keyword(s):

Positron Emission Tomography ◽

Brain Tumors ◽

Blood Brain Barrier ◽

Emission Tomography ◽

Brain Barrier ◽

Blood Brain ◽

Positron Emission ◽

The Mean ◽

Rubidium 82

✓ Hyperosmolar blood-brain barrier (BBB) disruption remains controversial as an adjuvant therapy to increase delivery of water-soluble compounds to extracellular space in the brain in patients with malignant brain tumors. To understand the physiological effects of BBB disruption more clearly, the authors used positron emission tomography (PET) to study the time course of BBB permeability in response to the potassium analog rubidium-82 (82Rb, halflife 75 seconds) following BBB disruption in anesthetized adult baboons. Mannitol (25%) was injected into the carotid artery and PET scans were performed before and serially at 8- to 15-minute intervals after BBB disruption. The mean influx constant (K1), a measure of permeability-surface area product, in ipsilateral, mannitol-perfused mixed gray- and white-matter brain regions was 4.9 ± 2.4 µl/min/ml (± standard deviation) at baseline and increased more than 100% (ΔK1 = 9.4 ± 5.1 µl/min/ml, 18 baboons) in brain perfused by mannitol. The effect of BBB disruption on K1 correlated directly with the total amount of mannitol administered (p < 0.005). Vascular permeability returned to baseline with a halftime of 24.0 ± 14.3 minutes. The mean brain plasma volume rose by 0.57 ± 0.34 ml/100 ml in ipsilateral perfused brain following BBB disruption. This work provides a basis for the in vivo study of permeability changes induced by BBB disruption in human brain and brain tumors.

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