Opening up the blood brain barrier
The brain sits cocooned behind a protective defense called the blood brain barrier. It’s there to protect the delicate neurochemistry of the nervous system and it bars the majority of chemicals - and critically drugs - from entering. Only very small molecules - like caffeine - can slip through. And this is a major frustration when it comes to developing treatments for diseases like Alzheimer’s, because it limits the repertoire of molecules that drug designers can work with. Unless, that is, you have a safe and selective way to temporarily open up the blood brain barrier and allow the right things in. Which is what James Choi at Imperial College London, and his colleagues have been trying to do. Chris Smith spoke with James to find out more...
James - Drugs have been developed over the past several decades and they work quite well in mice and in animal disease models but they can't get into the brain. What we're showing in this paper is a technology to get the drug into the brain.
Chris - But there are lots of drugs that do get into the brain extremely well - things like heroin, cocaine, nicotine, alcohol. They all do it, so what's the exception then?
James - So the exception is that those drugs, the bad drugs, are very very small, and so if you get a molecule small enough and put it into the bloodstream it'll get into your brain and everywhere else in your body. A lot of the drugs that are useful are bigger and so there's actually what we call a cut-off where we think with certainty that these drugs will not go across, and that includes antibodies, peptides.
Chris - And your challenge is to find a way to ease them into the brain and surmount this problem where at the moment they would struggle to get in?
James - Exactly. What we want to do is use a localised method to say ‘Hey, in this region such as your memory centre, which affects Alzheimer's disease, we want the drug only to go there.’ The way we do that, we inject tiny preformed micro bubbles - they're around the size of a red blood cell, and what we do is we apply a localised beam of sound onto the memory centre and the bubbles will then push the drugs from the blood into the brain.
Chris - But this is not new though is it, the idea of using injectable bubbles and then combining them with sound and directing that to the brain helps to dismantle this thing we refer to as the blood/brain barrier which keeps the blood space and the brain space separate, it does cause that to temporarily become permeable so drugs can go into the central nervous system. That's been done and that's been done quite a while ago, so are you doing it slightly differently then?
James - Yes. The current state of the art is to inject the micro bubbles and ping the bubbles with a very long pulse of ultrasound, and although they've done a lot of work to optimise it, the conclusion in the end is that the beam itself has some side-effects, and there's a list of issues. Two of the issues that we try to address is the distribution of the drugs. Within that beam the drugs accumulate in one area at a high concentration but it doesn't get to another area so it's a very uneven distribution. The second concern with long pulses is that it disrupts the blood/brain barrier for several hours and what that means is the blood/brain barrier can no longer do its original role which is to regulate what goes into the brain and what goes out, and so you allow a lot of the unwanted compounds into the brain.
Chris - A bit like jamming open the portcullis on the castle for longer than you'd like, so the good soldiers go in but then some other people sneak in behind them while the gates are still open?
James - Exactly. And so we want to make sure that we're disrupting the blood/brain barrier but do it in a very short time duration and so what we showed in this paper is that using short pulses of ultrasound in a very fast sequence we can get the blood/brain barrier open and then closed within 10 minutes.
Chris - And this works the same way does it? You're using the sound to shake the bubbles, the bubbles shake the blood vessels effectively and open up a temporary sort of permeability in this blood/brain barrier so that the bigger things that would normally be excluded can for a short while sneak in?
James - Yes, and the key thing here is to shake these bubbles gently.
Chris - And when you do this, how much can you enhance the delivery of a drug that would not previously stand any chance of getting into the central nervous system? How much more gets in if you do this?
James - A lot more. One of the model drugs that we tested does not go through the blood/brain barrier but with our technique it can then go in there so as a measure of how much more, that's really hard to decide if the original amount was very, very low. What we do know is that the level that we're delivering the drugs is at a similar dose to the long pulse sequences and a lot of work with the long pulses have shown that the dose is enough to have a therapeutic response against a disease such as Alzheimer's disease and Parkinson's disease.