Ultrasound: A Novel Method of Treating Brain Tumors by Traversing the Blood Brain Barrier
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Introduction
The Blood Brain Barrier (BBB) is an essential network of blood vessels and tissues that protects the central nervous system (CNS) from pathogens and neurotoxic substances. The blood vessels are reinforced with endothelial cells, a single cell layer which regulates the exchange between the bloodstream and the tissues in the vicinity. A cellular junction forms between the adjoining endothelial cells, its membranes fusing together in order to form an impermeable barrier to fluid or other substances. Also referred to as “tight junctions”, the endothelial cells in the BBB are situated closely from one another in order to strictly control the permeability of the blood vessels. Such regulation is necessary to protect the brain from toxic substances or harmful pathogens, supplying the brain with its crucial nutrients while filtering the harmful compounds back to the bloodstream.
Under regular circumstances, drugs and antibiotics are diffused across a cell membrane from an area of high concentration to low concentration. The rate of diffusion is dependent on the molecule’s lipid solubility, however, as the phospholipid bilayer of the membrane is composed of nonpolar (having no charge) fatty acid “tails” made of lipids. The rate is reliant on the molecule’s size as well, since smaller non-polar molecules are better able to diffuse through the tightly-packed lipid bilayer than the larger particles. On the other hand, the BBB has lower permeability due to its tight junctions, the plasma membrane of the endothelial cells joining together in order to disallow pathogenic substances from diffusing into the cell. As a result, a multitude of drugs and antibiotics fail to cross the plasma membrane and are ineffective when treating neurological conditions.
It has been a prevalent problem in the field of medicine, therefore, to attempt to tackle neurodegenerative disorders with the use of antibiotics and drugs due its inability to enter the nervous system.
In an attempt to allow the antibiotics to cross the BBB, a group of scientists crossed the frontier of modern medicine by utilizing ultrasound to allow the chemotherapeutic drug into the human brain by temporarily opening its protective shield, possibly resulting in new methods of treatment for those with brain cancer.
What is the Blood Brain Barrier?
The Blood Brain Barrier, also known as the BBB, is an essential structure that manages the entry of vital substances and nutrients into the brain while barricading harmful toxins or substances in the bloodstream. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, only allowing certain molecules to enter the brain tissue. The tight junctions only allow small, fat-soluble molecules to pass easily through the capillary wall, allowing essential non-polar molecules to easily cross the blood vessels and enter the brain. Other fat-soluble substances—such as caffeine and alcohol—are also able to enter the barrier due to the substances being non-polar, sharing similar characteristics with the membrane’s phospholipid bilayer. If the brain is in need of specific nutrients, the endothelial cells themselves can release peptidases or enzymes that can inactivate proteins or neurotoxic substances that may threaten the homeostasis of the brain.
Crossing the Blood Brain Barrier
Effective treatments of brain cancer currently do not exist, as (1) another mass tends to regrow in its place subsequent to surgical removal and (2) the chemotherapeutic drugs are ineffective due to their inability to reach the brain tissue. This is especially a problem with glioblastoma, a form of brain tumor that is prone to regrowth even after its removal. In fact, neurosurgeon Adam Sonabend of the Northwestern University Feinberg School of Medicine in Chicago states, “There’s really no established treatment for when the tumor comes back.” Unfortunately, patients with recurrent glioblastomas “don’t have meaningful therapeutic options, so we are exploring new ways to treat them.”
Until recently, patients with glioblastoma would typically receive a relatively weak chemotherapy drug that can bypass the brain’s barricade after the initial tumor has been removed. But due to its ineffectiveness, relentless research has been continued for the field until a new exploratory method has succeeded—using ultrasound to briefly open the BBB. A patient would first receive an intravenous injection of a fluid with microscopic bubbles, thus filling the body’s blood vessels when entered. Subsequently, the ultrasound waves would make the microbubbles vibrate, opening the densely packed blood vessel walls.
To examine the safety and the efficacy of the method, 17 patients had their regrown tumor removed and an ultrasound device implanted in their skull. During each session, participants received pulses of ultrasound waves for nearly five minutes while simultaneously being injected with microbubbles for thirty seconds. The ultrasound waves were able to reach a specific area of the brain encompassing the tumor cavity, penetrating nearly 8 centimetres deep into the brain tissue. Subsequent to the treatment was a 30 minute intravenous infusion of paclitaxel, a chemotherapeutic drug used to treat various forms of cancer.
Surprisingly, researchers found nearly four times as much paclitaxel in the targeted brain tissue compared with tissue outside of range. Further test cases with MRI scans and a special dye divulged that the BBB mostly returned to its normal state within an hour. Some side effects were also recorded amongst the patients, including headaches and confusion.
Scientists hope that this novel treatment will assist in extending the median life spans of glioblastoma patients subsequent to diagnosis, ranging approximately 14.6 months as of now. Paediatric radiation oncologist Cheng-Chia Wu from the Columbia University Irving Medical Center states, “This definitely is a very interesting paradigm that can be applied not just to glioblastoma but other brain tumors.” Despite its proven efficacy in treating brain tumors, Wu emphasizes that continuous tests should be run before they are properly utilized in treatments.
Citation
https://www.sciencenews.org/article/ultrasound-chemotherapy-drug-human-brain
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292164/
https://www.youtube.com/watch?v=e9sN9gOEdG4
https://www.youtube.com/watch?v=eakL-xHwWL4&t=334s
https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-020-00230-3
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