University of Maryland School of Medicine,
Keywords: MRI, ultrasound
Summary:In the age of new and promising medical discoveries and treatments being reported on a near-daily basis, few developments have been as transformative and far-reaching as combining state-of-the-art magnetic resonance imaging (MRI) and non-invasive energy deposition using focused ultrasound (FUS). Today, MRI-guided FUS (MRgFUS) continues to make headlines, where new indications for treatment are being proposed and developed at top medical research institutions around the world. MRgFUS is a new, disruptive technology that allows the controlled, targeted application of ultrasound energy deep within the body. Ultrasound energy can be tuned to create mechanical and/or thermal effects in tissues leading to a multitude of potential therapeutic benefits. These include direct lesion ablation, immune activation, and a host of transient structural effects that alter tissue permeability for improved delivery of therapeutics, from small molecules to monoclonal antibodies, viral and non-viral gene vectors, nanoparticle drug carriers and even cells. Over the last decade, MRgFUS has gained FDA approval for thermal ablation of uterine fibroids, prostate and breast cancer, as well as palliative treatment of bone metastases. Most recently, it was approved for the treatment of Essential Tremor (ET), a debilitating neurological condition involving dysfunctional neural circuits that is currently treated with surgically-implanted deep brain electrodes in more severe cases. The noninvasive MRgFUS procedure involves transcranial exposures for the ablation of the ventricular intermediate nucleus (VIM), located within the thalamus. The ability to safely treat the VIM for ET has created the opportunity to apply ultrasound for other brain-related applications, including enhanced therapeutic delivery. Working with the Dept. of Neurosurgery at our university, our team is leading efforts in the United States for using MRgFUS to enhance delivery to invasive brain tumors (glioblastoma, GBM), including the first FDA-approved clinical trial for opening the blood-brain barrier (BBB) in patients with GBM. In the context of this broader MRgFUS program, we have established methods for pre-clinical studies using patient-derived xenograft and genetically engineered rat brain tumor models that closely resemble invasive human GBM, and multi-transducer animal MRgFUS systems, similar to the clinical systems. This presentation will review the state-of-the-art MRgFUS technology in the context of its current clinical use. This will be followed by a review of our preclinical MRgFUS program and a discussion on how these treatments can enhance the delivery of both systemically and locally administered agents in the brain, by increasing extravasation and interstitial transport, respectively. Relevant details will also be provided on the biophysical mechanisms of ultrasound-tissue interactions for generating the cytoarchitectural changes that enable these results.