Break out the bubbles - delivering cancer drugs using external magnets

3 November 2016



Scientists at Singapore’s Nanyang Technological University (NTU) have created magnetic microbubbles that can target and deliver cancer drug particles with the aid of an external magnet. Medical Imaging Technology discusses the research with Dr Xu Chenjie, assistant professor at the institution’s School of Chemical and Biomedical Engineering.


Chemotherapy, while often ultimately effective, is a highly destructive, inefficient method of fighting cancer. It is non-targeted, often destroying healthy as well as cancerous tissue, and large amounts of the drug are flushed away quickly by the liver and lungs. The dose that remains often fails to penetrate certain kinds of malignant tissue, particularly brain tumours, which are protected by the blood brain barrier. On top of that is a long list of potential side-effects that can make the treatment as much of an ordeal for patients as the cancer itself.

Over their 50-year history, microbubbles – tiny globules just 100th the diameter of a human hair – have been a revelation as a contrast agent in magnetic resonance imaging, particularly in the cardiovascular field. In recent years, they have been successfully applied in numerous other ways, not all medical, such as helping to help clean up fouled water and allowing ships to glide more easily through the sea by creating a bed of air between their hulls and the water’s surface. The ultimate application for them, in the eyes of most medical researchers, is as a drug delivery system that can prove more penetrative and cause less collateral damage than chemotherapy.

The basic principle is as follows. The cancer drug is dissolved in a polymer shell, which coats the microbubble and gives it shape. The bubbles are released and then propelled through the body by ultrasound. Once they get to the target, most likely a tumour, the ultrasound power is turned up, causing the bubbles to vibrate, which releases drug molecules at the exact spot where they can have the greatest impact. Accuracy can be increased by placing molecules on the bubbles that bind with the tumour molecules. The idea came about through watching bubbles oscillate under a microscope, and the realisation that surface particles could detach from bubbles at high enough speeds to penetrate tissue, “like a bullet”, as one researcher noted.

While full of promise, the idea has had some significant barriers to overcome, and will have to pass many more tests before clinical application is a possibility. Bubbles in the blood can be very dangerous, as in cases of decompression sickness, or the bends (which tends to affect astronauts and divers), where rapid changes in pressure cause nitrogen bubbles to form, potentially blocking vital vessels.

Microbubbles must therefore be smaller than the smallest blood vessel in the body, and coated to stop them coalescing into potential obstructions. They have to be rigid enough to avoid premature bursting, but delicate enough to react to the ultrasound boost. They also have to be identical, so you know exactly how they will behave when inserted into the stream.

In 2013, researchers from Imperial College London and the University of Oxford made a significant breakthrough in this area which laid the groundwork for the advancements seen since. It had long been difficult to observe how microbubbles in the blood behaved under ultrasound, which is vital if you are to create the best formula in which to dissolve the cancer drugs and ensure the therapy produces repeatable results.

The researchers had the idea of adding a glowing molecule just beneath the other shell of the bubble, allowing them to observe their behaviour in detail using microscopes.

One of the lead scientists, Dr Marina Kuimova, from the Department of Chemistry at Imperial College London, said at the time: “The new technique could have a big impact on our understanding of how microbubbles interact with living cells and each other in blood vessels.

“We can now begin work on how to manipulate, or manufacture bubbles for use in medical treatments.”

Once the microbubbles are made and you know they respond well to ultrasound, a way must still be found of directing them to the right place in the body and releasing their payload without causing any collateral damage. Given the potential force generated by each pop, this is no easy task.

“Let’s look at the brain, for example, where there are a lot of blood vessels, but only part of the tissue is diseased,” says Dr Xu Chenjie, assistant professor at Nanyang Technological University in Singapore. “We are using bubbles to generate holes everywhere. Of course, it helps the drugs diffuse into the right regions, but those other areas are also affected by the drug. That’s the first problem. The second is that you are generating holes, causing damage to the blood vessels. How do you know if they will heal?”

Magnetic solution

Recent research by Dr Xu’s team at Nanyang has shed some light on these questions in a paper entitled ‘Controlled Nanoparticle Release from Stable Magnetic Microbubble Oscillations’, published in April 2016 in NPG Asia Materials. In order to target the drugs more accurately, the cancer drug was mixed with iron oxide nanoparticles, creating a magnetic microbubble coating.

External magnets, rather than ultrasound, were then used to direct these bubbles towards tumours. Once the bubbles were clustered around a growth, ultrasound was introduced and the bubbles began to vibrate, releasing the cancer drug exactly where it was needed, limiting damage to surrounding healthy tissue. The study took two and a half years, and involved 12 scientists from NTU (including a handful of undergraduates), City University of Hong Kong, and Tel Aviv University.

Doxorubicin – a commonly used chemotherapy drug containing polylacticcoglycolic acid particles – was delivered by targeted microbubble into the heart tissue of a zebrafish and the tumour tissue of a mouse with respective 18-fold and five-fold improvements in penetration. The drugs reached depths equivalent to 50 cell layers, or around 200μm. To achieve this level of penetration would normally require a high dose of drugs to be injected directly into the tumour: a painful, expensive process with a number of unwelcome side-effects.

“We spent a lot of time trying to push this idea, which came up with around April 2013,” says Xu. “At the beginning, we didn’t believe it would work, so we tried a lot of animals, as you can see in the paper.

“It has been pretty frustrating along the way, setting up the equipment for the tumour’s parameters, but I would say it’s a happy ending and we have something that is working. We’ve shot not only images, but also video. The public is interested and a company is also interested.”

Using external magnets to direct the bubbles was apparently quite straightforward, depending on the application of a simple magnetic field. The difficult part was creating a stable bubble and getting the right combination of cationic and ionic particles to prevent it from disintegrating before it could arrive at its target. This meant employing a mix of magnetic nanoparticles and functional molecules encased by cationic nanoparticles – for example, creating fluorescent microbubbles by combining fluorescent silica and iron oxide nanoparticles. This is a very precise process, but very slow, as the microbubbles have to be produced one by one.

The new technique could have a big impact on our understanding of how microbubbles interact with living cells and each other.

“The biggest challenge of this project is the stability of the bubbles,” says Xu. “Our bubble was mainly formed because of this electric interaction: cationic particles, self-assembled with an ionic surfactant. The drug particles are imbedded in the shell. Even today, we haven’t fully addressed the problem, but compared with the beginning it’s much better.

“In the beginning, when we mixed a bubble with blood it went ‘poof’ right away because there are many proteins in blood, but we managed to control the ratio between the cationic and ionic components.”

Beyond brain tumours

This work could represent a big step forward in efforts to develop effective, yet non-invasive, drug-delivery methods. It’s also potentially very cost-effective, requiring only the right chemical mix, an ultrasound machine and some magnets.

Xu’s team is working with a corporate partner to develop chemical formulations that employ the next generation of cancer therapeutics, a process that will broaden the possibilities of this drug delivery vehicle. “In the paper we use traditional therapeutics like doxorubicin,” he says. “The company is saying it’s not exciting, and there are other options.”

The team is also considering applications beyond the treatment of brain tumours (which were the initial target because of the problems associated with getting cancer drugs to penetrate the blood brain barrier).

Gene therapy is a particularly interesting potential application, given the difficulties of getting DNA to the right parts of the body. More violent bubble oscillations, produced by higher doses of ultrasound, could also be used to dissolve blood clots if sufficiently well targeted.

The team will now test the microbubble delivery method on lung and liver cancer models on a number of other animal models before eventually moving onto clinical trials. It hopes that the technique will be ready for use in hospitals in around eight years’ time.

“We don’t know what it would be most effective against,” Xu says. “By working with this company, we think there are a lot of other things you can do in addition to cancer.

“The main goal for this technology is to improve the penetration of the particles, and there are a lot of places you can go with this kind of concept, not necessarily just tumours.”  

As well as addressing tumours, microbubbles also have potential gene therapy applications.
Dr Xu Chenjie is assistant professor at Nanyang Technological University’s School of Chemical and Biomedical Engineering. He obtained his BSc at Nanjing University in 2002, after which he was a visiting scholar in the molecular imaging programme at Stanford before completing his PhD at Brown University.
Microbubbles could revolutionise non-invasive drug delivery techniques.


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