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How could we use microbubbles to fight cancer?

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Cancer cells

You could fit ten thousand microbubbles into a single full stop. But now a team of researchers at Leeds is hoping to use these tiny bubbles as a drug delivery device to treat cancer and other serious diseases.

Microbubbles, as the name suggests, are very small bubbles - just one-thousandth of a millimetre across. Researchers at Leeds think that they could have a big impact on the way we treat some of our most serious illnesses.

Microbubbles are already used in medicine to improve the use of ultrasound imaging - they reflect soundwaves better than human tissue and can be injected into a patient’s bloodstream to improve the images produced from an ultrasound scan.

The bubbles move around the body and eventually burst without causing any damage. This has led a team at Leeds to look at whether these bubbles could be filled with more than just harmless gas. Researchers at the University believe that if these bubbles carry medication they could deliver drugs directly to cancerous tumours.

Targeted treatment

Currently, if a patient is receiving chemotherapy they will have drugs injected into their bloodstream to fight the tumour. But these drugs – designed to attack and kill cancer cells – spread around the patient’s body, causing damage to healthy cells and causing the well-known side effects of chemotherapy – fatigue, hair loss and nausea.  

Traditionally, when you inject chemotherapies you get a lot of toxicity because the drug is effectively going everywhere, and these are very toxic drugs

says Professor Stephen Evans who is leading a team of researchers from across the University to look at how microbubbles could help to make this process less unpleasant for the patient.

We have people based in physics, which is my group, people in engineering and then people in medicine, and we came together to develop a project to aid the therapeutic delivery of drugs to tumours.

The idea that Leeds researchers are working on is to use microbubbles as a vehicle to carry these harmful drugs around the body, contained in even smaller packages called liposomes, which stop the drugs from harming the healthy cells. 

The bubbles can then be burst remotely using ultrasound to release the drug in precisely the right place. Microbubbles have the added advantage that as they burst they can temporarily break down the cell tissue in the tumour, delivering the medicine directly into the tumour cells. 

Pop the bubbles!

Micro-doses in microbubbles

Professor Evans explains that using microbubbles can have a big impact on the way chemotherapy works:

We can use a lot less of a drug or we can use more toxic drugs and the combination of those means that we would be able to significantly reduce the side effects of chemotherapy. There are drugs that have demonstrated great potential for tackling cancer but have been left on the shelf because they're currently too toxic to use.

The early results have been extremely promising and a study of the use of microbubbles on colorectal cancer has recently been submitted for publication. Professor Evans explains:

We've done it with two drugs so far, both targeted against colorectal cancer. In one case we see that if we use the bubble plus the ultrasound we effectively stop the tumour growing, whereas if we use the drug alone the tumours still carry on growing.

Leeds is well placed to carry out this research with innovative work taking place in medicine, physics and engineering which mean that we are creating new techniques in every part of the process – starting with the bubbles themselves.

Cancer cells

HORIZON machine

Horizon machine

The microbubbles currently used in medicine are made of a lipid shell – a naturally occurring fatty substance which doesn’t dissolve easily in liquid – and filled with different gases depending on what they are being used for. 

To use them to treat cancer, a single dose of medicine would require 10 million of these individual bubbles and it’s important that they are of similar size, with similar amounts of the drug contained in them. 

To make this process as efficient as possible, researchers within physics have created the HORIZON machine which produces the microbubbles. The machine is – appropriately – small and portable and can produce up to a billion of the bubbles in just a few minutes, more than enough for the researchers’ purposes. 

The machine is designed to produce the bubbles with the desired drugs and targeting agents – which makes the bubble more likely to concentrate in a particular area of the body – already included. The idea is that the whole process could be made as easy as slotting in the materials a patient needs and letting the machine produce the treatment. Professor Evans explains:

We have this idea - rather like one of these coffee machines where you put a sachet in and you get your different flavours out. What we want is to be able to put a sachet in depending on the drug type that you want or depending on whether you want your bubbles to target a particular type of cancer.

Hitting the right note

Leeds researchers are also pioneering the way the treatment is released when the microbubbles reach the tumour. As the bubbles travel through the patient’s bloodstream, researchers will use an ultrasound scanner to track them, with the advanced technology used at Leeds producing much more detailed imaging allowing doctors to see tumours in more detail than previously possible.

And when the ultrasound scan shows that the bubbles have reached the site of a tumour, the ultrasound can be switched to deliver a destruction pulse which allows researchers to burst them at exactly the right spot. Professor Evans explains:

A bit like how an opera singer can crack a wine glass by hitting a certain note with their voice, we can use a specific ultrasound amplitude or frequency to pop the bubbles as they reach the right place in the body.

Cancer cells

New ways to test treatments

Finally, Leeds has innovative tools which enable us to test these processes. Researchers are using “organoids” to test the microbubble treatment. These are miniature versions of human organs which are created on plastic chips with cancerous cells in them, Professor Evans explains: 

You could have a chip for almost every organ and then start to link these chips together so if we made an organ which was mimicking our colon we might then, behind that, have a liver organoid.

Researchers can test the use of microbubbles on these organoids and see whether it has an effect on the tumour but also if it has any unwanted side-effects.

Then as we introduce the drugs into the tumour with our microbubbles we can see the effects of whether we destroy or kill that tumour, but actually we can also then follow that drug around into the liver organ or see if it's having any detrimental effects that we might not want on the liver.

Expanding the bubble

The potential of microbubbles in medicine goes beyond cancer and Leeds researchers are excited about the possibilities for this type of treatment for a number of different conditions. 

One idea is that the bubbles could be filled with antibiotics and used to treat an infection in a specific area of the body. Professor Evans hopes that this could be particularly useful for infections in people who have implants, such as pacemakers, or are undergoing long term intravenous injections:

If somebody has an implanted device that becomes infected we believe that we can burst these bubbles in a way that can break up the bacterial biofilms that are growing. When antibiotics fail, often they do so because they can't get to the bacteria that they need to get to, whereas we believe bursting the bubble actually releases a lot of energy and it not only breaks up those bacterial films but it actually helps the drug to penetrate much deeper. We see that from the cancer work and we want to extend that into other areas.

Other researchers are also watching the results of the research closely to see whether the process could be used in their area of medicine. Professor Evans explains that the procedure might be able to be used to treat conditions which restrict blood flow to a foetus during pregnancy:

One of our clinical colleagues saw the work on the treatment of cancer and said: "well, could you put oxygen inside these bubbles?" So the idea is using oxygen-based bubbles as smaller mimics of blood cells, to deliver oxygen to help overcome these problems.

Cancer cells

Moving forward

The team are working towards being able to start clinical trials and although they are a still some time away from treating patients, they are very optimistic about the direction of the project.

Researchers are enjoying working with colleagues across the University - it’s not often that such a diverse team of researchers work together on one project like this, right from the basic science through to treating patients. Professor Evans says:

The post-doctoral researchers and PhD students in the team love this project because of the diversity of the people that are required to deliver the goal. I think we're very proud of the project and we're keen to move it on towards real treatments for patients. To be doing that at Leeds is great.

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