Optimizing how medications reach the brain     

​

Host Amber Smith: Upstate Medical University in Syracuse, New York, invites you to be The Informed Patient, with the podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith.

When cancer spreads to the brain, it is notoriously difficult to treat because of the blood-brain barrier, which limits the delivery of therapeutic agents to the brain.

Here to talk about how to optimize drug delivery in these situations is Dr. Satish Krishnamurthy. He's a professor of neurosurgery at Upstate.

Welcome back to "The Informed Patient," Dr. Krishnamurthy.

Satish Krishnamurthy: Thank you so much, Amber. I'm looking forward to this.

Host Amber Smith: Well, before we get into it, can you please describe what the blood-brain barrier is?

Satish Krishnamurthy: That's a very, very important question. A blood-brain barrier is like our walls and the front door of our house.

So the brain needs protected space, in the sense that the chemicals that affect the brain and the nerve transmission signals, as well as the environment that is protected, the temperature control, all needs to be perfect because the brain is very important for survival. If you can't think properly, whether you're in the jungle or in the ocean, you're going to be dead.

So brain function needs to be protected very closely. And in order to protect this, there are multiple mechanisms that protect us. And one of the most important ones is what is called a blood-brain barrier.

Blood-brain barrier prevents chemicals that we ingest in terms of food or other things that we inhale, either intentionally or unintentionally. These things get into the blood. And if everything that gets into the blood gets into the brain, then there'll be a problem with the brain, the functioning, the ability to protect, the ability to think, the ability to discern, all of that.

Therefore, biology has devised this blood-brain barrier, where substances in the blood don't get into the brain very easily. However, when you're treating brain disorders, you need to give medications to relieve the problem. For example, in this particular instance, if you have a tumor, you need to treat the tumor using a medication. And the medications taken either by mouth or given through infusion into the vein do not always get to the tumor in adequate concentrations to kill the tumor cells.

So blood-brain barrier becomes a very important barrier to delivering the drugs. So what protects us also prevents chemicals that we use to treat tumors not get in.

Host Amber Smith: So it protects what's inside the brain from coming out, and it protects things from outside the brain from coming in?

Satish Krishnamurthy: Right. The first part is the heart of my work over the last decade and a half. So it's like your front door, if you think of the analogy, right? If somebody knocks on the door, you don't like their looks or you don't want to answer, you don't open the door. So that blood-brain barrier is functioning.

That's the blood side. Outside is the blood side.

If you get into the house and somebody's inside, the first thing you do is open the door, throw the person out and close the door. So it works much better from inside than from outside. You can open the door much better from inside.

So there are mechanisms for this, and what we found in our work as to how "garbage" that is inside the brain -- meaning the breakdown products of cells, the proteins that get into the brain -- how do they get out from the brain into the blood? That was what we were working on when we were looking at finding treatments for hydrocephalus (excess fluid in the brain). In that pursuit, what we found was, there are channels, there are pathways that permit removal of the garbage material, or the protein material, from the brain side to the blood side around the blood-brain barrier. It's the same cells that pick up the proteins and other things and throw them out into the blood, where it can be excreted through the kidneys.

We used a method by which we put in a tube called a catheter into the brain, into a space in the brain called the ventricles. These ventricles are fluid spaces that are in everybody, and the fluid is very controlled in terms of its chemical composition, in terms of it production, and it's very important to nourish the brain as well as help it grow, from when we were little babies to adulthood.

So what we found was when we put chemicals in the brain ventricles, they would go around the blood vessels. So what we said was, since tumors have a lot of blood vessels around them, we thought it may be a good idea to put the chemicals that are used in the treatment of these tumors into the ventricles so that they can go in higher concentrations.

In order to test this, we decided to conduct experiments where we put in chemicals into the ventricles and decided to examine how much of these chemicals are getting into the tumor as opposed to the brain. Because these chemicals can also hurt the brain, we need to have a difference in the amount of chemicals that is distributed in the brain tumor versus the brain tissue.

What we found was that the tumors, because they have a higher amount of blood vessels, these chemicals delivered through what we call intraventricular drug delivery, which is what I described before, is very effective in increasing the amount of drug to the tumor, but not the brain.

Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith. I'm talking with Dr. Satish Krishnamurthy. He's a professor of neurosurgery at Upstate.

So let me make sure I understand this. You use a catheter to get from outside the brain into the ventricle space inside the brain, and that's how you put the medication in.

And then you leave it to biology to disseminate that medication through the blood vessels to the tumors.

Satish Krishnamurthy: Think of it as you don't breathe through your chest wall, right? You breathe through the nose, and it automatically goes to the lungs and does whatever exchange happens in the blood, right, from the lungs to the blood.

It's just like that. Use the biological mechanisms to deliver the drug to the tumor. And this is a common procedure that we do in a lot of my patients. It's a very common procedure to put a tube into the brain, into the ventricle, and we can either put a reservoir, which is a small bubble or like a port, into the head, where they can inject medications at different times to deliver the drugs.

It's called an Ommaya reservoir. And these reservoirs are commonly used to collect the samples or give drugs into the brain.

Host Amber Smith: Now, would this work on primary tumors that start in the brain, as well as tumors that develop when cancer spreads from somewhere else in the body?

Satish Krishnamurthy: Well, the answer for this is not yet known.

I think, it is a factor of blood vessels. Right now, the results from the experiments basically suggests that if there are a lot of blood vessels in the tumor, then this method will work. However, there are other ways of delivering drugs to the tumor.

We can increase the potential of delivery to the tumor by modifying the chemicals that we use. For example, you can use specific compounds called vectors, which will deliver the chemicals to the particular cells, if you will. And there are technologies that are available out there that can use this.

We have done the initial experiments that'll show that this may be an alternative approach that can specifically treat all kinds of tumors, and not just tumors, but all kinds of other disorders. Because what we have shown is that these chemicals are distributed widely, not only in the brain, but in the cranial nerves, the nerves that are coming from the brain, the nerves that are coming from the spine, and the spinal cord.

And the spinal cord itself. So this is an extremely valuable tool in, our opinion, to distribute drugs within the central nervous system.

Host Amber Smith: Now, you've written papers about this that have been published in medical journals. Are you hearing from colleagues about these techniques?

Satish Krishnamurthy: Some. We have some collaborations, both here at Upstate and at Wayne State University (in Detroit). We are very excited. It's not widely known, although we publish articles, there are so many articles that are published, it's not very widely known. But of course, having, you interview me and focus on this work, is going to be tremendously valuable for the visibility of our research. And I would like to thank you for that.

Host Amber Smith: Well, I want to ask you a little bit more about the blood-brain barrier. This is a physical barrier that goes around the entire brain. What does it look like? What does it feel like?

Satish Krishnamurthy: It's a physical barrier, but it's not like a membrane or a skin covering or anything like that.

This is a barrier that goes along the blood vessels. There is the heart, which is big and easily seen. And then there are arteries, and these arteries branch, and they branch, and they branch. Then they get into the brain. And they are very, very tiny. They are micrometers -- they are 1,000th of a millimeter -- wide. You're looking at measurements that are very, very small when they get to the cells.

So this barrier goes along the blood vessels. It's a cellular layer that is actually supported by a small, thin basement membrane, which is micrometers thick. So it's not a physical membrane. Think of it more like a barrier like the lungs, right? There is air that goes in, but air bubbles don't go into the blood. That's dangerous. It can kill you, right? There is a partition, what's called the interface. And probably the best way to say this junction where the blood and the brain meet is a blood-brain interface, just like the lung-blood interface. We have a lot of interfaces like that. So it's not a physical barrier.

And I think a lot of things change in the transport processes and everything. As you know, it's a different function when we are in the mother's womb, and it's a different function when we come out. It changes as we age, or if we have other disorders, like diabetes or Alzheimer's.

And you see that as a change in the function of the blood-brain barrier components or brain injury. Sometimes the tumors hijack some of these systems for their own benefit.

Host Amber Smith: So would that potentially change the way you treat someone, depending on the quality or the age of their interface if they're older and maybe it doesn't work as well?

Satish Krishnamurthy: The answer should be yes. But we lack the methods to determine how a change in the blood-brain interface is going to affect what we are doing. That's the heart of my work, where I'm trying to figure out how chemicals go in, how chemicals come out and how to change the way, to help our patients.

Like, for example, if you have hydrocephalus, there's less clearance of the proteins through the blood-brain interface. So we need to make it go faster. But it's a disadvantage when you're treating tumors. The drug should stay in for a longer time, right, inside the brain, for it to be effective.

So we should be able to control that like you would control an engine or an aircraft or something like that, which is our goal.

Can we do that? We don't know, but it's definitely a goal that is worth pursuing.

Host Amber Smith: Well, it's very interesting, and I'm glad to know that you're working on this. Thank you so much for sharing.

Satish Krishnamurthy: Absolutely. It's been my pleasure. Thank you so much for bringing focus onto this part of my research.

Host Amber Smith: My guest has been Dr. Satish Krishnamurthy. He's a professor of neurosurgery at Upstate. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe, with sound engineering by Bill Broeckel and graphic design by Dan Cameron.

Find our archive of previous episodes at upstate.edu/informed.

If you enjoyed this episode, please tell a friend to listen too, and you can rate and review "The Informed Patient" podcast on Spotify, Apple Podcasts, YouTube or wherever you tune in.

This is your host, Amber Smith, thanking you for listening.