Focused ultrasound for intracrainial drug delivery is a non-invasive technique that uses high-frequency sound waves (focused ultrasound, or FUS) to disrupt tight junctions in the blood–brain barrier (BBB), allowing for increased passage of therapeutics into the brain. The BBB normally blocks nearly 98% of drugs from accessing the central nervous system, so FUS has the potential to address a major challenge in intracranial drug delivery by providing targeted and reversible BBB disruption. Using FUS to enhance drug delivery to the brain could significantly improve patient outcomes for a variety of diseases including Alzheimer's disease, Parkinson's disease, and brain cancer.
Ultrasound is commonly used in the medical field for imaging and diagnostic purposes. With FUS, a curved transducer, lens, or phased array is used to guide the ultrasound waves to a particular location, similar to the way a magnifying glass can focus sunlight to a single point.Meng, Y., Hynynen, K., & Lipsman, N. (2020). Applications of focused ultrasound in the brain: from thermoablation to drug delivery. Nature Reviews Neurology, 17(1), 7–22. https://doi.org/10.1038/s41582-020-00418-z. This strategy concentrates the acoustic energy in a small target area while having a minimal effect on the surrounding tissue.Burgess, A., & Hynynen, K. (2013). Noninvasive and Targeted Drug Delivery to the Brain Using Focused Ultrasound. ACS Chemical Neuroscience, 4(4), 519–526. https://doi.org/10.1021/cn300191b. Depending on the acoustic parameters, FUS can be used to exert mechanical and/or thermal effects on target tissues, making it a versatile and promising tool for many therapeutic applications.
Blood–brain barrier
The BBB is a highly specialized structure composed of endothelial cells, pericytes, and astrocytic processes and is situated between the cerebral capillaries and brain parenchyma. The endothelial cells form tight junctions, creating a semi-permeable membrane that separates circulating blood from the central nervous system. Various mechanisms are used to transport molecules across the BBB. Small polar molecules such as glucose, amino acids, and nucleosides enter the brain through carrier-mediated transport. Small lipophilic molecules and gaseous molecules such as oxygen and carbon dioxide can passively diffuse through the BBB. Large molecules such as proteins and peptides use receptor-mediated or absorption-mediated endocytic transport to access the brain.Wong, A. D., Ye, M., Levy, A. F., Rothstein, J. D., Bergles, D. E., & Searson, P. C. (2013). The blood–brain barrier: an engineering perspective. Frontiers in Neuroengineering, 6. https://doi.org/10.3389/fneng.2013.00007.
The BBB is crucial for structural and functional brain connectivity and plays a major role in protecting the brain from circulating pathogens.Chen, K.-T., Wei, K.-C., & Liu, H.-L. (2019). Theranostic Strategy of Focused Ultrasound Induced Blood-Brain Barrier Opening for CNS Disease Treatment. Frontiers in Pharmacology, 10. https://doi.org/10.3389/fphar.2019.00086. However, the BBB is also a key impediment for intracranial drug delivery and significantly limits entry of therapeutic molecules into the brain. Generally, only lipid-soluble molecules with a low molecular weight (around ~400 Da) and a positive charge can cross the BBB.Bellettato, C. M., & Scarpa, M. (2018). Possible strategies to cross the blood–brain barrier. Italian Journal of Pediatrics, 44(S2). https://doi.org/10.1186/s13052-018-0563-0. Many therapeutic molecules do not have these properties and thus have difficulty entering the brain. For example, doxorubicin, a common chemotherapeutic, is ~540 Da in size and trastuzumab, a monoclonal antibody, is 148 kDa in size.Meng, Y., Suppiah, S., Surendrakumar, S., Bigioni, L., & Lipsman, N. (2018). Low-Intensity MR-Guided Focused Ultrasound Mediated Disruption of the Blood-Brain Barrier for Intracranial Metastatic Diseases. Frontiers in Oncology, 8. https://doi.org/10.3389/fonc.2018.00338. The molecular weight of these molecules significantly hinders their ability to pass through the tight junctions present in the BBB.
Since the BBB limits the bioavailability of therapeutics in treating neurological diseases, many strategies have been developed to circumvent the BBB. Osmotic agents disrupt the BBB by causing osmotic shrinkage of the endothelial cells and creating an osmotic pressure gradient.Rodriguez, A., Tatter, S., & Debinski, W. (2015). Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment. Pharmaceutics, 7(3), 175–187. https://doi.org/10.3390/pharmaceutics7030175. However, this strategy results in global rather than localized BBB opening which can lead to neurological deficits and seizures.Gumerlock, M., Belshe, B., Madsen, R., & Watts, C. (1992). Osmotic blood–brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: patient series and literature review. Journal of Neuro-Oncology, 12(1). https://doi.org/10.1007/bf00172455. Intracranial injections can be used to directly deliver drugs to a specific part of the brain.Duskey, J. T., Belletti, D., Pederzoli, F., Vandelli, M. A., Forni, F., Ruozi, B., & Tosi, G. (2017). Current Strategies for the Delivery of Therapeutic Proteins and Enzymes to Treat Brain Disorders. International Review of Neurobiology, 1–28. https://doi.org/10.1016/bs.irn.2017.08.006. While these injections limit systemic toxicities and remove the loss of drug from first pass clearance, these procedures are invasive and can pose additional risk to the patient. Convection enhanced delivery uses an intracranial catheter to deliver drug through the interstitial spaces of the central nervous system. This strategy is also quite invasive as it requires insertion of the catheter into the brain and the diffusion of drug from the catheter tip is limited.Ferguson, S. D., Foster, K., & Yamini, B. (2007). Convection-enhanced delivery for treatment of brain tumors. Expert Review of Anticancer Therapy, 7(sup1), S79–S85. https://doi.org/10.1586/14737140.7.12s.s79. Radiation therapy is known to increase BBB permeability, but the temporal characteristics of radiation-induced opening are unpredictable and radiation can damage the surrounding brain tissue by causing necrosis, demyelination, and gliosis.Rubin, P., Gash, D. M., Hansen, J. T., Nelson, D. F., & Williams, J. P. (1994). Disruption of the blood–brain barrier as the primary effect of CNS irradiation. Radiotherapy and Oncology, 31(1), 51–60. https://doi.org/10.1016/0167-8140(94)90413-8. Focused ultrasound has the potential to address the limitations posed by these strategies by offering a method for non-invasive, temporally-controlled, and localized BBB disruption.
Thermal and cavitation assisted FUS-induced BBB opening Early studies that investigated the use of FUS for BBB disruption used ultrasound to increase the permeability of the blood vessels either by increasing the temperature (usually to 40-45°C) or forming gas bubbles (inertial cavitation). While these studies concluded that this method could be used to open the BBB, damage to healthy tissue was always reported.Mesiwala, A. H., Farrell, L., Wenzel, H. Jurgen., Silbergeld, D. L., Crum, L. A., Winn, H. Richard., & Mourad, P. D. (2002). High-intensity focused ultrasound selectively disrupts the blood–brain barrier in vivo. Ultrasound in Medicine & Biology, 28(3), 389–400. https://doi.org/10.1016/s0301-5629(01)00521-x. In 2004, it was discovered that the threshold for thermal BBB disruption is greater than the threshold for thermal damage, meaning thermal BBB disruption cannot be performed without causing some damage to the brain tissue. Nevertheless, ultrasound hyperthermia may still be useful for intracranial drug delivery. In vitro studies showed that moderate ultrasound hyperthermia (temperature elevations ≤ 6°C) increases endothelial cell permeability to hydrophobic molecules.Cho, C., Liu, Y., Cobb, W. N., Henthorn, T. K., Lillehei, K., Christians, U., & Ng, K. (2002). Pharmaceutical Research, 19(8), 1123–1129. https://doi.org/10.1023/a:1019837923906. FUS hyperthermia has also been used with radiation therapy to treat patients with brain tumors since FUS sensitizes tumor cells to radiation by inhibiting DNA damage repair and disrupting the protein kinase B signaling pathway.Guthkelch, A. N., Carter, L. P., Cassady, J. R., Hynynen, K. H., Iacono, R. P., Johnson, P. C., Obbens, E. A. M. T., Roemer, R. B., Seeger, J. F., Shimm, D. S., & Steal, B. (1991). Treatment of malignant brain tumors with focused ultrasound hyperthermia and radiation: results of a phase I trial. Journal of Neuro-Oncology, 10(3). https://doi.org/10.1007/bf00177540.Man, J., Shoemake, J. D., Ma, T., Rizzo, A. E., Godley, A. R., Wu, Q., Mohammadi, A. M., Bao, S., Rich, J. N., & Yu, J. S. (2015). Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling. Cancer Research, 75(8), 1760–1769. https://doi.org/10.1158/0008-5472.can-14-3621. Studies have also shown that FUS can be used to both thermally ablate brain tumors and improve delivery of chemotherapy through reversible BBB opening to kill any remaining malignant cells.McDannold, N. J., Vykhodtseva, N. I., & Hynynen, K. (2006). Microbubble Contrast Agent with Focused Ultrasound to Create Brain Lesions at Low Power Levels: MR Imaging and Histologic Study in Rabbits. Radiology, 241(1), 95–106. https://doi.org/10.1148/radiol.2411051170. However, since thermal BBB disruption cannot be induced without damaging tissue, it may not be useful for non-cancer applications in which preserving healthy tissue may be essential.