Intracranial applications of magnetic resonance-guided focused ultrasound

Lipsman N, Mainprize TG, Schwartz ML, Hynynen K, Lozano AM. Intracranial
applications of magnetic resonance-guided focused ultrasound. Neurotherapeutics.
2014 Jul;11(3):593-605.

Abstract

The ability to focus acoustic energy through the intact skull on to targets millimeters in size represents an important milestone in the development of neurotherapeutics. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel, noninvasive method, which--under real-time imaging and thermographic guidance--can be used to generate focal intracranial thermal ablative lesions and disrupt the blood-brain barrier. An established treatment for bone metastases, uterine fibroids, and breast lesions, MRgFUS has now been proposed as an alternative to open neurosurgical procedures for a wide variety of indications. Studies investigating intracranial MRgFUS range from small animal preclinical experiments to large, late-phase randomized trials that span the clinical spectrum from movement disorders, to vascular, oncologic, and psychiatric applications. We review the principles of MRgFUS and its use for brain-based disorders, and outline future directions for this promising technology.
 

From the paper:

BBB Disruption

The BBB is composed of tightly bound capillary endothelial cells and is the brain’s primary defense against large and molecularly heavy toxins. This dense capillary network, which is lined by a continuous layer of epithelial cells, provides a broad barrier system, prohibiting the passive and active transport of large and potentially harmful molecules.Tight junctions between capillary endothelial cells further limit the transport of molecules between cells, ensuring that access to the central nervous system is transcellular. Therefore, passage across the BBB is by diffusion for small molecules or receptor-mediated for larger molecules. This rigid, size, charge and biochemically mediated barrier has hampered the development of neurotherapeutics for brain cancer, and also for other neurodegenerative conditions such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). A potentially promising application of MRgFUS is the ability to temporarily disrupt the BBB, thus facilitating the passage of compounds too large to otherwise pass into the brain. Such compounds can include chemotherapy agents, as well as monoclonal antibodies. The last decade has seen significant advances in this area, with preclinical models demonstrating 1) that MRgFUS can open the BBB temporarily while not generating a lesion or irreversible damage; 2) that chemotherapy agents can get into the brain in concentrations that correlate with the time that the BBB was open; 3) that temporary BBB opening is safe in small- and medium-sized animals; and 4) that it is possible to achieve significant levels of concentration in various types of tumors, including gliomas and brain metastases .

 

BBB disruption can be achieved using a combination of MRgFUS at low frequencies and the simultaneous administration of contrast agents containing microbubbles. The interaction of acoustic energy and microbubbles at the capillary endothelial cells results in temporary disruption of the BBB and diffusion of large molecules. The precise mechanisms underlying MRgFUS-mediated BBB disruption are under active investigation. Preclinical models suggest that temporary disruption of the BBB is likely the result of stable bubble oscillations, induced by the interaction of low acoustic power with preinjected microbubbles at the surface of capillary endothelial cells. Bubble oscillation and growth results in stretching of endothelial cell membranes, thus permitting transient opening of the BBB within seconds of the start of the sonications. The opening is healed within approximately 6 h, although longer openings of 24 h and longer have been reported and are presumably associated with more serious tissue effects. In animal models, a wide range of molecules, varying in size, have been transported across the BBB following MRgFUS-mediated disruption (see below). In general, these long-term studies have shown that the effects of MRgFUS BBB disruption on brain tissue is minimal, with negligible neuronal damage, no evidence of ischemia or apoptosis, no extravasation of erythrocytes, and no damage to sonicated tissue.

Using these approaches, several groups have shown that MRgFUS-mediated BBB disruption can achieve significant intratumoral and tissue concentrations of several key chemotherapeutic agents, including Herceptin (Roche, Basel, Switzerland), doxorubin and temozolamide (TMZ). In one study, Kinoshita et al. used a mouse model to show Herceptin concentrations in target tissue were significantly correlated with the extent and duration of MRgFUS-mediated BBB disruption. Wei et al. used a glioma rat model to study concentrations of TMZ and tumor progression after MRgFUS-mediated BBB disruption. The authors found that compared with TMZ administration alone, chemotherapy plus MRgFUS resulted in greater cerebrospinal fluid concentrations of TMZ and reduced 7-day tumor progression rates. Using doxorubicin and MRgFUS BBB disruption in a rat model, Treat et al. also found similar effects on glioma progression, with modest effects on survival. These results provide proof of concept that MRgFUS-mediated BBB disruption is possible, and can achieve significant brain tissue concentrations of complex and large biologic agents. Such findings suggest that MRgFUS may be used either alone or as adjunctive therapy for patients undergoing surgical resection of primary or secondary brain malignancy. As a result, several human trials are currently underway to explore the use of MRgFUS for brain tumor therapy.

 

Courtesy of:  http://insightticker.com/2015/11/11/1776/neuroscientists-breach-brain-barrier-to-treat-sick-patients/