Increased Vascular Permeability

Physiological barriers exist between the interior of blood vessels and their surrounding tissue, which can limit delivery of drugs to their intended targets. Focused ultrasound can reversibly increase the permeability of blood vessel walls, thereby temporarily allowing drugs to pass through them and into the surrounding tissue1.

The delivery of drugs across vessel walls is limited primarily by a network of endothelial cells joined by tight junctions2. The mechanical effects of focused ultrasound disrupt these tight junctions to increase permeability3. Microbubbles can also be used to better control this process to reduce the risk of damage to the vessel4.

This same effect has been used to open the blood-brain barrier, a particularly dense barrier of cells that severely inhibits the diffusion of many drugs and gene therapies into the brain. In a preclinical setting, focused ultrasound coupled with injected microbubbles has been used to transiently open this barrier and enable delivery of various compounds into the brain1,4,5. The blood-brain barrier has been shown, via both MRI and histological analyses, to revert to its original structure without permanent damage within four hours after the end of the sonication4.

This technique could enable more effective pharmacological treatment of tumors throughout the body, and through blood-brain barrier opening, the treatment of various neurological disorders such as Parkinson’s disease, Alzheimer’s disease, and glioblastoma1,6–8.

[1] C. X. Deng, “Targeted drug delivery across the blood-brain barrier using ultrasound technique.,” Ther. Deliv., vol. 1, no. 6, pp. 819–848, Dec. 2010. References:

[2] González-Mariscal L, Nava P, Hernández S. Critical role of tight junctions in drug delivery across epithelial and endothelial cell layers. J. Membr. Biol. 2005;207:55–68.

[3] 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. 

[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] J. Park, Y. Zhang, N. Vykhodtseva, F. A. Jolesz, and N. J. McDannold, “The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound.,” J. Control. Release : Off. J. Control. Release Soc., vol. 162, no. 1, pp. 134–142, Aug. 2012. 

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

[7] 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.

[8] 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.