Affordable stereotactic-guided focused ultrasound device for tunable drug delivery to the mouse brain

Abstract Introduction Intra-arterial (lA) delivery of therapeutic agents across the blood-brain barrier (BBB) is an evolving strategy which enables the distribution of high concentration therapeutics through a targeted vascular territory, while potentially limiting systemic toxicity. Studies have demonstrated lA methods to be safe and efficacious for a variety of therapeutics. However, further characterization of the clinical efficacy of lA therapy for the treatment of brain tumors and refinement of its potential applications are necessary. Methods We have reviewed the preclinical and clinical evidence supporting superselective intraarterial cerebral infusion (SSJACI) with BBB disruption for the treatment of brain tumors. In addition, we review ongoing clinical trials expanding the applicability and investigating the efficacy of lA therapy for the treatment of brain tumors. Results Trends in recent studies have embraced the use of SSIACI and less neurotoxic chemotherapies. The majority of trials continue to use mannitol as the preferred method of hyperosmolar BBB disruption. Recent preclinical and preliminary human investigations into the lA delivery of Bevacizumab have demonstrated its safety and efficacy as an anti-tumor agent both alone and in combination with chemotherapy. Conclusion lA drug delivery may significantly affect the way treatment are delivered to patients with brain tumors, and in particular GBM. With refinement and standardization of the techniques of lA drug delivery, improved drug selection and formulations, and the development of methods to minimize treatment-related neurological injury, lA therapy may offer significant benefits for the treatment of brain tumors.

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Characterization of ultrasound-mediated delivery of trastuzumab to normal and pathologic spinal cord tissue

Scientific Reports ◽

10.1038/s41598-021-83874-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Paige Smith ◽

Natalia Ogrodnik ◽

Janani Satkunarajah ◽

Meaghan A. O’Reilly

Keyword(s):

Drug Delivery ◽

Spinal Cord ◽

Focused Ultrasound ◽

Healthy Tissue ◽

Spinal Cord Tissue ◽

Sprague Dawley ◽

Intense Staining ◽

Her2 Breast Cancer ◽

Sprague Dawley Rats ◽

Blood Spinal Cord Barrier

AbstractExtensive studies on focused ultrasound (FUS)-mediated drug delivery through the blood–brain barrier have been published, yet little work has been published on FUS-mediated drug delivery through the blood-spinal cord barrier (BSCB). This work aims to quantify the delivery of the monoclonal antibody trastuzumab to rat spinal cord tissue and characterize its distribution within a model of leptomeningeal metastases. 10 healthy Sprague–Dawley rats were treated with FUS + trastuzumab and sacrificed at 2-h or 24-h post-FUS. A human IgG ELISA (Abcam) was used to measure trastuzumab concentration and a 12 ± fivefold increase was seen in treated tissue over control tissue at 2 h versus no increase at 24 h. Three athymic nude rats were inoculated with MDA-MB-231-H2N HER2 + breast cancer cells between the meninges in the thoracic region of the spinal cord and treated with FUS + trastuzumab. Immunohistochemistry was performed to visualize trastuzumab delivery, and semi-quantitative analysis revealed similar or more intense staining in tumor tissue compared to healthy tissue suggesting a comparable or greater concentration of trastuzumab was achieved. FUS can increase the permeability of the BSCB, improving drug delivery to specifically targeted regions of healthy and pathologic tissue in the spinal cord. The achieved concentrations within the healthy tissue are comparable to those reported in the brain.

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Investigations into the use of MRI-controlled focused ultrasound for hyperthermia-mediated drug delivery

10.1063/1.4757362 ◽

2012 ◽

Author(s):

Robert Staruch ◽

Rajiv Chopra ◽

Kullervo Hynynen

Keyword(s):

Drug Delivery ◽

Focused Ultrasound

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Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia

Nature Communications ◽

10.1038/s41467-021-21022-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Carmen Gasca-Salas ◽

Beatriz Fernández-Rodríguez ◽

José A. Pineda-Pardo ◽

Rafael Rodríguez-Rojas ◽

Ignacio Obeso ◽

...

Keyword(s):

Parkinson’S Disease ◽

Drug Delivery ◽

Parkinson's Disease ◽

Side Effects ◽

Neurodegenerative Disorders ◽

Focused Ultrasound ◽

Temporal Cortex ◽

Clinical State ◽

Cognitive Improvement ◽

Bbb Opening

AbstractMR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and brain tumors. MRgFUS could become a therapeutic tool for drug delivery of putative neurorestorative therapies. Treatment for Parkinson’s disease with dementia (PDD) is an important unmet need. We initiated a prospective, single-arm, non-randomized, proof-of-concept, safety and feasibility phase I clinical trial (NCT03608553), which is still in progress. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipito-temporal cortex where cortical pathology is foremost in this clinical state. Changes in β-amyloid burden, brain metabolism after treatments and neuropsychological assessments, were analyzed as exploratory measurements. Five patients were recruited from October 2018 until May 2019, and received two treatment sessions separated by 2–3 weeks. The results are set out in a descriptive manner. Overall, this procedure was feasible and reversible with no serious clinical or radiological side effects. We report BBB opening in the parieto-occipito-temporal junction in 8/10 treatments in 5 patients as demonstrated by gadolinium enhancement. In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS-BBB opening in PDD is thus safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of BBB opening for drug delivery to treat dementia in PD and other neurodegenerative disorders.

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