Emerging Applications of Therapeutic Ultrasound in Neuro-oncology

Abstract

Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain. Technological advances, including phased array transducers and real-time temperature monitoring with magnetic resonance (MR) thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest, as FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to (1) generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; (2) enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier and/or improving distribution through the brain extracellular space; and (3) modulate the tumor microenvironment in order to generate an immune response. In this review, we describe each of these applications for FUS, the proposed mechanisms of action, and the preclinical and clinical studies that have set the foundation for utilizing FUS in neuro-oncology.

The Future of Cranial Neurosurgery—Adapting New Approaches

“…2 Over the last 20 yr, ultrasound engineering has exponentially improved, eliminating the need for a bone defect and improving the accuracy of FUS. 3 Much like laser interstitial thermal therapy (LITT), the emergence of magnetic resonance imaging (MRI) has facilitated monitoring of FUS-guided thermal ablation fields. [4][5][6] As a result, modern MRFUS (MR-guided focused ultrasound) techniques have been developed and applied to a wide variety of neurological and nonneurological disorders including uterine fibroids and prostate cancer.…”

“…These pulsed acoustic waves can generate a wide host of other target effects, among them the induction of microbubbles that resonate, producing internal cavitation on a microscopic level and the propagation unidirectional forces that can induce microshearing of target tissues. 3 These purported tissue-sparing (nonablative) techniques are believed to facilitate other functions of MRFUS including blood-brain barrier (BBB) disruption, immunomodulation, and improved chemoradiosensitivity.…”

“…This type of therapy, termed sonodynamic therapy, utilizes chemotherapeutics to augment the cytotoxicity of ultrasonic therapy. 3 Drugs such as doxorubicin, 5-ALA, porphyrins, and curcumin all can be converted into higher energy states after exposure to FUS which can thereby induce free radical formation and eventually the apoptotic cascade.…”

Focused ultrasound stimulates ER localized mechanosensitive PANNEXIN-1 to mediate intracellular calcium release in invasive cancer cells

“…High-intensity (>5 W/cm 2 ) continuous FUS generates a systemic immune stimulatory effect resulting in tumor ablation (Lu et al, 2009). Pulsed FUS (i.e., non-continuous stimulus to minimize heat generation) (Hersh et al, 2016) may induce a more refined cellular/molecular immune response, (Ziadloo et al, 2012) by initiating inflammatory responses which boost cancer immunotherapy (Curley et al, 2017;Mauri et al, 2018). FUS may thus offer a new approach to overcome cancer immune-resistance, a well-known limitation preventing more wide-spread clinical adoption of successful immunotherapies such as CAR T cells (Caliendo et al, 2019;Tokarew et al, 2019).…”

Ultrasound-Based Therapies for the Treatment of Cancer

“…Safe, localized and reversible BBBD with MRgFUS offers a significant advantage over current methods to bypass the BBB and extends the use of many drugs that do not cross the BBB [292][293][294] . Large, biodegradable polymeric nanoparticle delivery systems can provide sustained drug release while limiting both systemic and local toxicities 13 .…”