Could microscopic bubbles hold the key the more effective cancer treatments?
The deadliest bullet in the world is just a lump of metal without a suitable weapon that can fire it accurately at a target. In a similar way, powerful cancer-killing viruses have failed to live up to expectations because of difficulties in targeting them effectively at tumours.
Known as adenoviruses, they’re usually responsible for giving us colds by infecting the cells in our noses and throats, although in some people they can cause more severe problems.
For several years, researchers have been busy developing modified adenoviruses that specifically infect and multiply inside tumour cells. Then they burst out in search of new hosts, destroying the cancer cells in the process.
It’s a neat idea – a cancer treatment that attacks tumours and amplifies itself within the patient, but leaves healthy tissue unharmed. However, getting it to work in reality has been rather more tricky.
This is because it’s difficult to get the viruses into cancer cells if they’re injected into the bloodstream, as the immune system quickly tries to get rid of the infection. Injecting viruses directly into tumours has had more success, but it’s a difficult and invasive procedure.
Some researchers have tried to get round the problems by injecting larger doses of viruses. But this leads to a dangerous buildup of virus particles in the liver. Instead, Cancer Research UK-funded Professor Len Seymour in Oxford and his colleagues are trying a different approach, publishing their findings in the Journal of the National Cancer Institute.
First disguise your virus…
We’ve previously described how Professor Seymour and his team developed a ‘stealth’ disguise for viruses designed to target ovarian cancer, to help it evade detection by the immune system.
The results from lab studies were promising, but there’s still a problem. Although the coating, made from sticky molecules called polymers, protects the viruses it also makes it harder for them to infect cancer cells.
In this new paper, the researchers have gone a step further and designed a polymer stealth coat that falls off the virus when it encounters a slightly acidic environment compared to the rest of the body – exactly the kind of environment that’s found immediately around tumours.
This is because cancer cells use up oxygen and generate energy in an abnormal way compared to healthy tissue, leading to a highly localised build-up of acid. [Note: No, this doesn't mean that an “alkaline diet” will help to treat cancer – physiology doesn't work that way.]
…Then reveal it
Experiments in the lab showed that a small drop in pH (i.e. the environment becoming more acidic) could make the virus shed its coat. Further tests with mice proved that the coated virus didn’t build up in the liver. But the bigger issue still remained – namely, how to get the viruses close to the cancer cells in the first place.
The blood vessels around tumours are chaotic and abnormal, making it tricky to get the viruses near them in a high enough dose to start an infection. As an aside, the same problem also affects chemotherapy drugs, something our researchers are also working on.
To solve this challenge, the scientists combined their ‘stealth viruses’ with another exciting technology: microbubbles.
First developed for medical use in the late 1990s to help improve the clearness of ultrasound imaging, microbubbles are tiny bubbles of gas that can be injected into a patient’s bloodstream.
Depending on the particular properties of the bubbles, they either ‘wobble’ or burst in the presence of ultrasound waves. It’s this second property – the ability to pop the bubbles on cue – which Professor Seymour and his team are now exploiting.
It turns out that when microbubbles burst, they generate a small shockwave that can help propel virus particles into a tumour – something the team has already proved works in lab tests.
To test this idea in real tumours, the researchers injected their stealth-coated virus into mice transplanted with breast cancer cells, along with a microbubble product called SonoVue. Then they targeted a short burst of ultrasound directly over the tumour.
The results were exciting – they saw levels of viruses in the ultrasound-treated tumours that they’d never managed to achieve in previous tests. Importantly, they also found that the viruses were shedding their stealth coats and starting to multiply in the cancer cells, just as they’d hoped. And, best of all, the virus therapy was working – although tumours didn’t completely disappear, their growth slowed down.
Forever blowing (micro)bubbles?
These early results are exciting, and suggest that the combination of stealth polymers, microbubbles and targeted ultrasound could help to overcome some of the difficulties that have dogged virus therapies for cancer.
There are several good points to this approach. Ultrasound is cheap and widely used in hospitals already. And SonoVue is already approved by the National Institute for Health and Care Excellence (NICE) for use in ultrasound imaging.
There are also some significant challenges that need to be addressed if the technique is to work in patients. For a start, there’s more work to be done to make sure that the coated virus and microbubble agent end up in the right place at the right time, so the ultrasound blast can do its work.
It’s also not clear whether ultrasound would have to be focused on each individual tumour, in cases where cancer had spread to many places, or whether larger areas or even the whole body could be treated.
For now, this is an important step forward in trying to harness the power of cancer-killing viruses. And it also provides useful knowledge that could help researchers developing nanoparticle-based cancer treatments, which suffer from similar problems with delivering their payload directly into tumours.
It’s also worth noting that these kinds of new approaches need scientists across many disciplines to work together – biologists, chemists, engineers and physicists all have a part to play. As well as our contribution, the Engineering and Physical Science Research Council (EPSRC), the Wellcome Trust and other charities and research organisations also helped to fund this research, and it involved scientists in the UK, Spain and the Czech Republic.
Cancer is too big a challenge for any one researcher, team or even funding organisation to tackle alone. We all have to work together to beat it.
- Carlisle R. et al. (2013). Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound., Journal of the National Cancer Institute, PMID: 24168971