Using nanoparticles to target paediatric brain tumours

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Published: 8 Feb 2016
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Dr Jordan Green - The Johns Hopkins University School of Medicine, Baltimore, USA

Dr Green talks to ecancertv at Children with Cancer UK’s workshop on Drug Delivery in Paediatric Brain Tumours in London, UK.

He discusses the research being conducted in his lab at The Johns Hopkins University School of Medicine that is using bioengineering approaches to develop novel nanotherapeutics.

My interests are in developing new types of enabling technologies to treat brain tumours. We do that by making new kinds of biomaterials that can safely and effectively deliver new types of biological agents such as nucleic acids to tumours without hurting normal cells in the brain.

Can you tell us more about the nanoparticles that your lab has been developing?

So they’re really small, it’s about the same dimension is a football is to the nanoparticle as the size of a football to planet Earth. So really small particles that can then go into brain cancer cells, specifically without going into and being effective or causing toxicity in healthy cells. What they’re made out of is a biodegradable plastic and it degrades in water into just small molecules that then get eliminated by the body safely. But what it does before it degrades is it can deliver new types of medicines that are different than conventional chemotherapies, that are much more specific, that can be biologically targeted to what makes cancer cancer. So we think that this type of approach can open up new avenues for treatment of all different types of cancers in the brain and that it has a much wider therapeutic window than conventional therapies that can hurt a lot of healthy cells as well as cancer cells.

How are you getting the nanoparticles into the brain tumours?

In our studies so far we’ve done studies in mice and rats where they’re directly injected into the brain. With some other work we have going on we’re looking at how they can be systemically administered and still get to the brain. But the initial work we’re doing is for local therapy and this is something that can be done maybe also following… if there’s surgery it could be done as a follow-up treatment at the same time to inject these particles in there or it could be a separate step to inject them.

What results have you obtained to date?

In these rodent models what we’ve seen is that we can see an extension in survival with these different approaches. So this gives us hope that it’s working but where we’ve developed it with this technology of the particles is we can change the cargos. So a lot of these are based on nucleic acids or gene therapy and the idea here is that we’re able to introduce new genes that may have been mutated in the cancer so we can reintroduce those that could cause those cancer cells to apoptose or new genes that would cause those cancer cells to be little factories that make chemotherapy right there to then destroy itself and the neighbouring cancer cells. Or to deliver nucleic acid signals that then direct resistant cancer cells to not be resistant any more to conventional therapies or radiation. So those are some of the different approaches. So the animal models and the models we look in vitro with cells from patients both look very promising so we’re excited to go to further steps.

What about using these nanoparticles in combination with other therapeutic approaches?

Yes, there’s good opportunities there. So what we find for example is that certain cancer cells have mutations that make them resistant to these standard therapies. So we can introduce new genetic information to programme those cells now to be very susceptible to those conventional treatments like radiation and chemotherapy. One of the things we’re also looking at is that it seems that with tumours they’re heterogeneous and there are some cells that look more stem cells, these punitive brain cancer stem cells are often resistant to these conventional treatments. But what we can do with our nanoparticles is we can then drive them to be more like the other cells that are very susceptible. Then when the conventional treatment comes they can get wiped out too, rather than be in this resistant fraction of cells that then persist and keeps growing.

What about the safety and practicalities of delivering genetic material into the brain?

Yes, there are a few sides to that. One is in terms of the polymers we’re using to the deliveries we have to make sure those are very safe. They’re similar to the types of materials that are used for, for example, biodegradable stiches, sutures or other things in the body that have been shown as very safe and they degrade in water in the body. Then the other side is the genetic material that we’re delivering. So it might be that certain RNA molecules might be preferable than DNA molecules but in any case what we’re delivering is something that maintains itself separately from the chromosome, it doesn’t integrate into the chromosome, it isn’t something that does a permanent change. It’s something that is just there transiently and then its effect is gone in a week or two. So it’s not something that is permanently changing the genetic information. But while it’s there for that week what it is doing is expressing factors, it’s getting that cancer cell to die and it’s doing it in a way where if it was delivered to off-target cells it wouldn’t have an effect in those cells, it would be very benign. Then again it would degrade or be silenced over time. So it’s a way that we think we can have more precision and we can also even do things in a more personalised way if we knew, by having a sample of the biopsy, for example, we can see what the genetic mutations are with that patient and then design a genetic therapy that would work accordingly. But this is all still very early preclinical work and one of the big challenges is to then have the funds to test these questions out and to ensure safety first. But that’s why we’re using a non-viral biodegradable safe material approach rather than a virus approach which is the other way a lot of work is going on in gene therapy. So instead of starting with a virus that has perhaps more safety concerns, we’re starting with a material that we know is safe and then working to design it to be more effective.

What does the future hold? What about clinical trials?

We’ve seen different signals of efficacy in these different animal models but what’s needed, for example in the States, would then be to do toxicology studies with GLP material in multiple, at least two, animal species. So this is something that would take further funding or investment to do to do that study. When that tox study is done, and very thoroughly, we know it’s very safe, then that’s when it could be done in initial clinical studies. So I’d say it’s still a few years away but it’s something that we do have promising early results. This is the type of therapy that is orthogonal to the current therapies so it’s something that can be used in combination and can be readily administered and so we’re excited about it.

What is your take-home message?

I think one of the things that’s great about this workshop and in this field in general is how different scientists with different backgrounds, for example my background is more in biomedical engineering, are able to work together with neurosurgeons and oncologists to discuss strategies and come up with new solutions. So I think that’s really exciting and having this kind of bringing together of different people, different backgrounds, I think is really important to innovate the solutions that are needed.