Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation

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 thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest because FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; to enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier or improving distribution through the brain extracellular space; and to modulate the tumor microenvironment 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 using FUS in neuro-oncology.

Abbreviations: BBB, blood-brain barrierCED, convection-enhanced delivery5-Ala, 5-aminolevulinic acidFUS, focused ultrasoundGBM, glioblastoma multiformeHSP, heat shock proteinMRgFUS, magnetic resonance-guided focused ultrasoundpFUS, pulsed focused ultrasound.

Figure 1

Applications of therapeutic ultrasound in neuro-oncology. Transcranial focused exposures may be used for thermal ablation, radiosensitization, sonodynamic therapy, BBB disruption, ultrasound-assisted local delivery, and immunomodulation. CED, convection-enhanced delivery; ROS, reactive oxygen species.

Figure 2

Effect of SDT in a rat C6 intracerebral glioma model. A, coronal brain sections depicting selective destruction of the tumor (outlined by the dashed circle) in the group treated with SDT (arrow). B, tumor size in coronal sections for each treatment group. An asterisk indicates statistical significance (P < .05) when compared to rats undergoing a sham operation. 5-Ala, 5-aminolevulinic acid; FUS, focused ultrasound; SDT, sonodynamic therapy. Modified with permission from Ohmura T, Fukushima T, Shibaguchi H, et al. Sonodynamic therapy with 5-aminolevulinic acid and focused ultrasound for deep-seated intracranial glioma in rat. Anticancer Res. 2011;31(7):2527–2533.

Figure 3

Ultrasound-mediated opening of the BBB. A, coronal brain sections depicting extravasation of Evans blue dye (EBD) following FUS-mediated opening of the BBB (scale = 5 mm). B, quantification of EBD concentration with or without FUS in normal rats (sonication produced a 3.8-fold increase, P < .001) and in rats with tumors (sonication produced a 2.1-fold increase, P = .09). C, axial, contrast-enhanced T1-weighted magnetic resonance imaging sequences demonstrating increased contrast-enhancement following sonication of a brain tumor in a rat (lower) relative to a tumor that did not undergo sonication (upper). D, CSF-to-plasma ratio of the TMZ concentration in animals treated with TMZ only or combined TMZ with FUS-BBB opening (TMZ + FUS). E, Kaplan-Meier plot demonstrating improved survival of animals in the TMZ + FUS group compared to control animals or those receiving TMZ of various doses alone. BBB, blood-brain barrier; EBD, Evans blue dye; FUS, focused ultrasound; TMZ, temozolomide. Modified with permission from Wei KC, Chu PC, Wang HY, et al. Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study. PLoS One. 2013;8(3):e58995.

Figure 4

Ultrasound-assisted convection-enhanced delivery (UCED) to the rodent brain. A, a plane wave transducer with a cannula through-hole is mounted on top of the rodent brain through a small craniotomy window in the skull. B, 3-dimensional reconstruction of the distribution of infused EBD with and without ultrasound exposure. C, brain slices in the cannula path showing EBD distribution with (lower) and without (upper) ultrasound exposure. CED, convection-enhanced delivery; EBD, Evans blue dye; UCED, ultrasound-assisted convection-enhanced delivery. Reproduced from Lewis GK Jr., Guarino S, Ghandi G, et al. Time-reversal techniques in ultrasound-assisted convection-enhanced drug delivery to the brain: technology development and in vivo evaluation. Proc Meet Acoust. 2011;11:20005–20031, with the permission of the Acoustical Society of America.