Focused Ultrasound-Mediated Blood-Brain Barrier Opening Increases Delivery and Efficacy of Etoposide for Glioblastoma Treatment

Wei, Hong-Jian; Upadhyayula, Pavan S.; Pouliopoulos, Antonios N.; Englander, Zachary; Zhang, Xu; Jan, Chia-Ing; Guo, Jia; Mela, Angeliki; Zhang, Zhiguo; Wang, Tony J. C.; Bruce, Jeffrey N.; Canoll, Peter; Feldstein, Neil A.; Zacharoulis, Stergios; Konofagou, Elisa E.; Wu, Cheng‐Chia

doi:10.1016/j.ijrobp.2020.12.019

Cited by 54 publications

(39 citation statements)

References 47 publications

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“…Enzymes quickly degrade drugs administered intranasally, and the clearing function of nasal cilia reduces the time that drug get contact with the nasal epithelial cells, which decreases drug absorption. Under appropriate parameters, FUS combined with microbubbles can open the BBB non-invasively, locally, and reversibly thus enhances the delivery of antibodies ( Jordão et al, 2010 ), neurotrophic factors ( Lin et al, 2016 ; Karakatsani et al, 2019 ), nanoparticles ( Ohta et al, 2020 ) and macromolecular drugs ( Park et al, 2017 ; Wei et al, 2021 ) to specific brain regions. Due to the drug’s short half-life, it is necessary to open the BBB to deliver the drug repeatedly.…”

Section: Discussionmentioning

confidence: 99%

Focused Ultrasound Promotes the Delivery of Gastrodin and Enhances the Protective Effect on Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

Wang

Luo

et al. 2022

Front. Cell. Neurosci.

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Parkinson’s disease (PD) is the second most common chronic neurodegenerative disease globally; however, it lacks effective treatment at present. Focused ultrasound (FUS) combined with microbubbles could increase the efficacy of drug delivery to specific brain regions and is becoming a promising technology for the treatment of central nervous system diseases. In this study, we explored the therapeutic potential of FUS-mediated blood–brain barrier (BBB) opening of the left striatum to deliver gastrodin (GAS) in a subacute PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration of GAS in the left hemisphere was detected by ultra-high performance liquid chromatography electrospray Q-Orbitrap mass spectrometry (UHPLC/ESI Q-Orbitrap) and the distribution of tyrosine hydroxylase (TH) neurons was detected by immunohistochemical staining. The expression of TH, Dopamine transporter (DAT), cleaved-caspase-3, B-cell lymphoma 2 (Bcl-2), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and synaptophysin (SYN) protein were detected by western blotting. Analysis showed that the concentration of GAS in the left hemisphere of PD mice increased by approximately 1.8-fold after the BBB was opened. FUS-mediated GAS delivery provided optimal neuroprotective effects and was superior to the GAS or FUS control group. In addition, FUS enhanced GAS delivery significantly increased the expression of Bcl-2, BDNF, PSD-95, and SYN protein in the left striatum (P < 0.05) and reduced the levels of cleaved-caspase-3 remarkably (P = 0.001). In conclusion, the enhanced delivery by FUS effectively strengthened the protective effect of GAS on dopaminergic neurons which may be related to the reinforcement of the anti-apoptotic activity and the expression of synaptic-related proteins in the striatum. Data suggests that FUS-enhanced GAS delivery may represent a new strategy for PD treatment.

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Section: Discussionmentioning

confidence: 99%

Focused Ultrasound Promotes the Delivery of Gastrodin and Enhances the Protective Effect on Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

Wang

Luo

et al. 2022

Front. Cell. Neurosci.

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“…Despite being non-invasive, MRI does not allow real time tissue sampling ( 58 ). Therefore, many studies implemented the use of passive cavitation detection (PCD) which can be used in real time to monitor the acoustic emissions of MBs ( 54 , 80 , 89 ). It can help to show if the cavitation produced is either stable or inertial.…”

Section: Bbb/btb Disruption and Evaluationmentioning

confidence: 99%

“…Besides, there is also a decrease in JAM-A, which is noted after LIFU+MBs mediated BBB/BTB disruption ( 30 ). These changes can be observed as early as 10-15 min following the procedure which increases as time passes by ( 47 , 59 , 77 , 93 ) showing a prolonged exposure ( 77 ), as well as retention and diffusion in targeted areas ( 38 , 54 , 71 , 74 ), which is independent of the drug concentration ( 77 ). This elevated level of drug in sonicated tumors could still be seen later, even when the drug concentration in plasma has decreased ( 47 ).…”

Section: Therapeutic Strategies Exploiting Lifu+mbs Based Targetingmentioning

confidence: 99%

Low-Intensity Focused Ultrasound Technique in Glioblastoma Multiforme Treatment

et al. 2022

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Glioblastoma is one of the central nervous system most aggressive and lethal cancers with poor overall survival rate. Systemic treatment of glioblastoma remains the most challenging aspect due to the low permeability of the blood-brain barrier (BBB) and blood-tumor barrier (BTB), limiting therapeutics extravasation mainly in the core tumor as well as in its surrounding invading areas. It is now possible to overcome these barriers by using low-intensity focused ultrasound (LIFU) together with intravenously administered oscillating microbubbles (MBs). LIFU is a non-invasive technique using converging ultrasound waves which can alter the permeability of BBB/BTB to drug delivery in a specific brain/tumor region. This emerging technique has proven to be both safe and repeatable without causing injury to the brain parenchyma including neurons and other structures. Furthermore, LIFU is also approved by the FDA to treat essential tremors and Parkinson’s disease. It is currently under clinical trial in patients suffering from glioblastoma as a drug delivery strategy and liquid biopsy for glioblastoma biomarkers. The use of LIFU+MBs is a step-up in the world of drug delivery, where onco-therapeutics of different molecular sizes and weights can be delivered directly into the brain/tumor parenchyma. Initially, several potent drugs targeting glioblastoma were limited to cross the BBB/BTB; however, using LIFU+MBs, diverse therapeutics showed significantly higher uptake, improved tumor control, and overall survival among different species. Here, we highlight the therapeutic approach of LIFU+MBs mediated drug-delivery in the treatment of glioblastoma.

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“…MRgFUS technology is gaining substantial interest for its ability to provide controlled, non-invasive, and targeted therapeutic ultrasound energy, which can be adjusted to create a variety of beneficial biological effects for treatments in the brain (52). These specific effects include destructive thermal ablation (53,54), radiosensitization (55), immune activation (56,57), BBB opening for therapeutic delivery (58,59), and stem cell homing (60,61).…”

Section: Mrgfus Technology and Clinical Applicationsmentioning

confidence: 99%

MRI Guided Focused Ultrasound-Mediated Delivery of Therapeutic Cells to the Brain: A Review of the State-of-the-Art Methodology and Future Applications

et al. 2021

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Stem cell and immune cell therapies are being investigated as a potential therapeutic modality for CNS disorders, performing functions such as targeted drug or growth factor delivery, tumor cell destruction, or inflammatory regulation. Despite promising preclinical studies, delivery routes for maximizing cell engraftment, such as stereotactic or intrathecal injection, are invasive and carry risks of hemorrhage and infection. Recent developments in MRI-guided focused ultrasound (MRgFUS) technology have significant implications for treating focal CNS pathologies including neurodegenerative, vascular and malignant processes. MRgFUS is currently employed in the clinic for treating essential tremor and Parkinson's Disease by producing precise, incisionless, transcranial lesions. This non-invasive technology can also be modified for non-destructive applications to safely and transiently open the blood-brain barrier (BBB) to deliver a range of therapeutics, including cells. This review is meant to familiarize the neuro-interventionalist with this topic and discusses the use of MRgFUS for facilitating cellular delivery to the brain. A detailed and comprehensive description is provided on routes of cell administration, imaging strategies for targeting and tracking cellular delivery and engraftment, biophysical mechanisms of BBB enhanced permeability, supportive proof-of-concept studies, and potential for clinical translation.

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Focused Ultrasound-Mediated Blood-Brain Barrier Opening Increases Delivery and Efficacy of Etoposide for Glioblastoma Treatment

Cited by 54 publications

References 47 publications

Focused Ultrasound Promotes the Delivery of Gastrodin and Enhances the Protective Effect on Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

Focused Ultrasound Promotes the Delivery of Gastrodin and Enhances the Protective Effect on Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

Low-Intensity Focused Ultrasound Technique in Glioblastoma Multiforme Treatment

MRI Guided Focused Ultrasound-Mediated Delivery of Therapeutic Cells to the Brain: A Review of the State-of-the-Art Methodology and Future Applications

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