Blood-Brain Barrier Opening

The blood-brain barrier (BBB) is a protective layer of tightly joined cells that lines the blood vessels in the brain and prevents harmful substances, such as toxins and infectious agents, from diffusing into the surrounding brain tissue.

Unfortunately, it also limits the amount of medication that can reach diseased brain targets. Safely and temporarily opening this barrier to deliver drugs in therapeutic concentrations to the brain is a long-sought goal for treating a wide range of neurologic conditions, including brain tumors, Alzheimer’s disease and epilepsy.

Focused ultrasound has been shown to disrupt the BBB in a non-invasive, safe, and targeted manner¹. It is capable of reliably producing a therapeutic window of up to four hours immediately after treatment^2,3.The mechanical effects of FUS, namely cavitation, are thought to be the principle cause behind this BBB disruption. Oscillating microbubbles in the vessels put pressure on the endothelium and force apart the tight junctions^2,4. Large amounts of energy are needed for FUS to induce cavitation on its own, and using such high energies can lead to many of the negative side effects seen in previous research. Instead, recent work has investigated coupling focused ultrasound with ultrasound contrast agents – also known as microbubbles. Injecting these pre-formed bubbles prior to FUS treatment reduces the energy needed to disrupt the barrier since the ultrasound no longer needs to generate the bubbles on its own. When this technique was compared to thermal ablation, it was found to use up to two orders of magnitude less energy⁵, which results in a reduced risk of unintended tissue damage⁶. 

This method of BBB disruption – FUS with microbubbles – has had very promising results. Normally only small molecules (typically smaller than 400 Da) with the proper charge and hydrophilicity can cross the BBB, but disruption of this barrier with FUS has been shown to enable molecules as large as 150 kDa to cross^7,8.

Temporary opening of the blood-brain barrier in a safe and targeted manner with focused ultrasound unlocks a vast array of potential treatments. Immunotherapies such as IL-12 or even entire immune cells, as well as chemotherapeutics, can be delivered to notoriously difficult to treat brain tumors with this technique^9-11. Various therapeutic drugs and molecules can be delivered for the treatment of depression¹², Parkinson’s disease¹³, and Huntington’s disease¹⁴ among many other neurological disorders. Even just opening the BBB may have therapeutic value for Alzheimer’s disease by reducing the amyloid plaque burden^15,16.

Webinars:

Focused Ultrasound for the Temporary Opening of the Blood-Brain Barrier by Elisa Konofagou, PhD, Columbia University

Suggested Reading: 

Blood-Brain Barrier State of the Field Report – November 2015

Facilitation of Drug Transport across the Blood–Brain Barrier with Ultrasound and Microbubbles by Stephen Meairs

Drug Delivery Across the Blood-Brain Barrier using Focused Ultrasound by Alison Burgess and Kullervo Hynynen

Drug and Gene Delivery Across the Blood-Brain Barrier with Focused Ultrasound by Kelsie Timbie, Brian Mead, Richard Price

References:

[1] Alonso, A. Ultrasound-induced blood-brain barrier opening for drug delivery. Front. Neurol. Neurosci. 36, 106–115 (2015).

[2] N. Sheikov, N. McDannold, S. Sharma, and K. Hynynen, “Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium.,” Ultrasound Med. & Biol., vol. 34, no. 7, pp. 1093–1104, Jul. 2008. 

[3] Downs, M. E. et al. Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task. PLoS ONE 10, e0125911 (2015).

[4] Y.-S. Tung, F. Vlachos, J. A. Feshitan, M. A. Borden, and E. E. Konofagou, “The mechanism of interaction between focused ultrasound and microbubbles in blood-brain barrier opening in mice.,” J. Acoust. Soc. Am., vol. 130, no. 5, pp. 3059–3067, Nov. 2011. 

[5] Vykhodtseva, N., Sorrentino, V., Jolesz, F. A., Bronson, R. T. & Hynynen, K. MRI detection of the thermal effects of focused ultrasound on the brain. Ultrasound Med. Biol. 26, 871–880 (2000).

[6] McDannold, N., Vykhodtseva, N., Raymond, S., Jolesz, F. A. & Hynynen, K. MRI-guided targeted blood-brain barrier disruption with focused ultrasound: histological findings in rabbits. Ultrasound Med. Biol. 31, 1527–1537 (2005). 

[7] Hynynen, K. et al. Focal disruption of the blood-brain barrier due to 260-kHz ultrasound bursts: a method for molecular imaging and targeted drug delivery. J. Neurosurg. 105, 445–454 (2006).

[8] Kinoshita, M., McDannold, N., Jolesz, F. A. & Hynynen, K. Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound. Biochem. Biophys. Res. Commun. 340, 1085–1090 (2006).

[9] Chen, P.-Y. et al. Focused ultrasound-induced blood–brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. J. Transl. Med. 13, (2015).

[10] Alkins, R. et al. Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res. 73, 1892–1899 (2013).

[11] Fan C-H, Ting C-Y, Chang Y-C, Wei K-C, Liu H-L, Yeh C-K. Drug-loaded bubbles with matched focused ultrasound excitation for concurrent blood–brain barrier opening and brain-tumor drug delivery. Acta Biomater. 2015;15:89–101.

[12] Tsai S-J. Transcranial focused ultrasound as a possible treatment for major depression. Med. Hypotheses. 2015;84:381–3.

[13] Samiotaki G, Acosta C, Wang S, Konofagou EE. Enhanced delivery and bioactivity of the neurturin neurotrophic factor through focused ultrasound—mediated blood–brain barrier opening in vivo. J. Cereb. Blood Flow Metab. 2015;35:611–22.[14] Burgess, A., Huang, Y., Querbes, W., Sah, D. W. & Hynynen, K. Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression. J. Control. Release Off. J. Control. Release Soc. 163, 125–129 (2012).

[15] Burgess, A. et al. Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology 273, 736–745 (2014).

[16] Leinenga, G. & Götz, J. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model. Sci. Transl. Med. 7, 278ra33–278ra33 (2015).