Bursting the bubble on cancer

How to take on the leading cause of death in the developed world? To go big, you need to start small thinks Professor Steve Evans as he takes us through the use of microbubbles in drug delivery…

How can a tiny bubble treat some of the most serious and complex diseases which humans suffer?

The answer is that to an extent they already do ­–­ microbubbles are 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.

However, I think these microbubbles have an even more valuable use: to carry drugs to specific parts of the body so targeting cancer tumours directly.

Microbubbles, as the name suggests, are very small bubbles ­– just one-thousandth of a millimetre across. At the moment, once they’re injected into the body, they circulate and eventually burst, delivering their harmless gas contents without causing any damage to healthy cells and organs. With some adaptation, they could do so much more; so, while I’m a physicist by trade, I’m working with engineers and health researchers on a programme to develop a new way to aid the therapeutic delivery of drugs to tumours using them.

Our plan is to develop systems to precisely measure the dose of drugs required for delivery direct to the site of the tumour via the microbubbles, place them safely into measured bubbles and insert them into the body before tracking them to the right place. We’ll then use ultrasound to burst them, so the payload is delivered to the right location on a tumour.

In contrast, at present, when a patient receives chemotherapy they have drugs injected into their bloodstream to fight the tumour. These drugs are designed to attack and kill cancer cells as they spread around the patient’s body, but they damage healthy cells and cause well-known side effects in the process.

It could be as easy as slotting in the medicines a patient needs and letting the machine produce the treatment, like the coffee machines where you put a pod in and get various flavours out

The advantage I’ve already found with microbubbles is that when they burst, they can temporarily break down the cell tissue in the tumour, delivering the medicine directly into the tumour cells.

It could have a big impact on the way chemotherapy works. Potentially we could use a lot less of a drug or we can use more toxic drugs; the combination of those means that we would be able to significantly reduce the side effects of chemotherapy. Also, 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 we’ve recently submitted a study of the use of microbubbles on colorectal cancer for publication. In that study we show that when bubbles plus the ultrasound were used, we effectively stopped the tumour growing, whereas if we used the drug alone the tumours carried on growing.

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 they are 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, my team has created the HORIZON machine to produce the microbubbles. It’s small and portable and can produce up to a billion of the bubbles in just a few minutes, more than enough for our purposes at this stage. The machine is designed to produce the bubbles with the desired drugs and targeting agents already included. The idea is that the whole process could be made as easy as slotting in the medicines a patient needs and letting the machine produce the treatment, like the coffee machines where you put a pod in and get various flavours out. What we want is to be able to put a pod or sachet in depending on the drug type required and whether the bubbles are aimed at a particular type of cancer.

Cancer and beyond

As well as developing and fine-tuning the machinery, we are also pioneering the way the treatment is released when the microbubbles reach the tumour.

As the bubbles travel through the patient’s bloodstream, we plan to 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. 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 us to burst them at exactly the right spot.

As well as developing all of this, we’re lucky at the University to already have the tools and systems in place to carry out the tests.

We’re creating ‘organoids’ ­– miniature versions of human derived tumours associated with different organs in the body, on plastic chips, to test the efficacy of our microbubbles and to ensure they don’t have any unwanted side effects. We already have convincing data that using microbubbles to treat cancer is scientifically and medically possible, but in time we believe that we can also expand the method to treat other illnesses.

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

For example, if somebody has an implanted device that becomes infected, we believe that we can burst our 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.

Equally, the procedure could be adapted to treat conditions which restrict blood flow to a foetus during pregnancy. One of my clinical colleagues saw our work on the treatment of cancer and asked if we could put oxygen inside the bubbles. Using them as smaller mimics of blood cells to deliver oxygen to help overcome these problems.

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

Lastly, I’ve got to put a word in for the post-doctoral researchers and PhD students who do all of the bench work, as well as our collaborators at the Medicines Discovery Catapult who are helping validate our results and push this work towards translation. We all benefit from working on a project which demands a diversity of disciplines to deliver a common goal. We're very proud of the project and are keen to move it on towards real treatments for patients.

Author: Professor Steve Evans is based at the School of Physics and Astronomy, University of Leeds