Nanoparticle chemotherapy cuts brain cancer relapse rate

Interview with Thomas Kisby, University of Manchester

Part of the show Chasing fire clouds, and nanoparticles blitz brain cancers

Surgery is often the first step in treating glioblastoma, the most aggressive form of brain cancer. But, even the most skilled surgeon cannot remove every cancerous cell, and the tissue left at the surgical margin is usually where the cancer returns. But now scientists have uncovered a promising way to close this gap, using drug-wrapped nanoparticles that can sneak into the brain post-op and blitz any residual cancer. It’s the brain child of Manchester scientist Tom Kisby…

Tom - We're trying to overcome one of the major problems in the care of patients who are diagnosed with glioblastoma, which is a very aggressive, invariably lethal brain tumour. Both these problems are related to the fact that the tumour is localised in the brain. The first one being that surgery is very difficult, so it's almost impossible to remove all of the tumour, meaning there will always be cancer cells left behind which can trigger recurrence, and this is exactly what happens in all patients within usually a few months after their surgery. The second problem, which is also related to the fact that these tumours occur in the brain, is because the brain is protected by the blood-brain barrier, which is a barrier that essentially stops toxins, chemicals, etc., getting into the brain. This means most cancer therapy drugs, chemotherapies, don't really get to the brain in significant amounts, and particularly in glioblastoma, once the tumour has been removed, don't seem to get there in any way that can be effective, meaning again, patients will ultimately, their tumours will grow back and at that point there's nothing that can be done.

Chris - How are you trying to surmount this?

Tom - So we spent a lot of time trying to come up with ways that we could get drugs into the brain. One of the most obvious is if you're doing a surgery, you remove the tumour and then you have access to the site potentially where those tumour cells are. However, there's a major delivery problem when you do that, which is that there's kind of a pressure and fluid gradient that pushes anything you put there out, and this is exactly what's happened when people have attempted these approaches. So we actually flipped to the other way around and questioned, okay, if we're injuring the brain, we're potentially inducing changes in this blood-brain barrier, so actually we could go through the bloodstream. So what we did is we investigated in the short time after surgery, if we administer, in our case, nanoparticles in the bloodstream, could we basically detect those entering the brain? And indeed, that's exactly what we found.

Chris - So you take advantage of the fact that the blood-brain barrier is temporarily dismantled by the surgical intervention to remove the tumour, and so you can use that window of opportunity to sneak these particles in there. What's in the particles then that makes them want to home into that bit of the brain?

Tom - So there's nothing specific in the particles we were using. So we were using what we called liposome nanoparticles, which are balls of fat. These are used in other types of cancer to deliver chemotherapies. In our case, at least at the start of our study, we just used empty nanoparticles just to show what they were doing. But what happens is, because they circulate for a long time in the bloodstream, we think they take advantage of the fact that the blood-brain barrier essentially is open or leaky or compromised, meaning they leak out into the brain, but because of their size, because they're not like a molecule that can quite easily move around, they then get stuck in the exact site, this exact site where injury has occurred, which is also the site for patients where their tumours typically recur.

Chris - And therefore you're going to concentrate them where the action was, which means if you have a drug in there, it would concentrate where the action was. You minimise side effects in the rest of the body and you get the drug where it does crucially need to go, to mop up any stray cancer your surgeons left behind.

Tom - Exactly, yes. So we do a comparison using these nanoparticles to deliver a common chemotherapy drug, doxorubicin, and we show if you administer the doxorubicin within the nanoparticle, within these specific time windows after surgery, you get a significant accumulation of the drug around the resection surgical margin. If you administer just the drug on its own, you basically don't see any of it going to the surgical margin, or at least it doesn't stay there, so it goes in and washes out and is metabolised by the body. So yeah, it's a much more targeted approach to therapy.

Chris - Have you got an actual way to test this though, or is this still test tube level?

Tom - No, so we've tested this in mouse models. So we have a mouse model of glioblastoma brain tumour surgical resection, so we can grow tumours in these animals, we come and do a second surgery to remove the tumour, and then we can administer either empty nanoparticles or nanoparticles containing these chemotherapy drugs and then measure the amount of drug that gets into the brain.

Chris - And how much better do the animals do, or how much delivery do you get, and do you get enough that were those tumour cells in a human, they would see enough drug to destroy meaningful numbers of them, so you would make a clinical difference to that outcome?

Tom - Yeah, so at least at the preclinical level in these mouse models, what we see is that if you administer mice with just doxorubicin on its own after surgical resection, you get a slight increase in their survival time, so essentially their time before their tumour starts to recur, of around say, a week. In the case of the lipid nanoparticles containing the doxorubicin, we actually see in one of our models complete prevention of recurrence in these animals, so none of them showed any signs of the tumours growing back, and then in a much more aggressive model, around 50% of them had complete responses, so this suggests indeed it makes enough of a difference to see a change at the preclinical level. Of course, clinically this needs to be tested in patients, but there's nothing to say that it couldn't make some kind of positive impact on patient outcomes.

Chris - Is it relatively translatable? Are these sorts of nanoparticles already used in other applications clinically, so you could just make up packaged up doxorubicin like this and apply your technique to the operating theatre tomorrow?

Tom - Yeah, so one of the key things we did in this particular study was to try and choose a nanoparticle that was immediately translatable, so the actual liposome nanoparticle we're using is a clinically used drug, it's called Caelyx or Doxil, and this is used for patients with ovarian carcinoma or ovarian cancer, and we basically repurposed it and applied it in this exact way, in this exact model, so there's nothing now stopping a clinical study taking place where people could administer this same drug off label for this different application.

Chris - That'll be outstanding if you can do that, because the prognosis for glioblastoma is pretty bleak isn't it?

Tom - Yeah, so less than 5% of patients will survive for five years or more, and most patients will die from the disease within around a year from diagnosis.