Using graphene to tackle cancer

Nanomaterials like graphene have the potential to offer advanced tools for the early diagnosis, progression and treatment of cancer. Kostas Kostarelos, Professor of Nanomedicine at The University of Manchester and Severo Ochoa Distinguished Professor at the Catalan Institute of Nanoscience and Nanotechnology (ICN2), tells us about his work in this area.

How is nanomedicine contributing to cancer research?

In terms of existing benefits to cancer patients, nanotechnology is being used to develop safer, more accurate tools and therapies, resulting in reduced drug toxicity and better targeting.

Traditionally, nanotechnology helped oncologists to deliver very effective therapeutics specifically or preferentially to cancer cells. Put more simply, you take a potent anti-cancer drug and package it in a nanoparticle, which then takes it to the cancer site by minimising damage to healthy cells. The first nanotechnology-based products were designed to achieve this - targeting cancers and delivering the therapeutic agent with less cytotoxic effects.

A good, early example of this is a liposome, a spherical nanoparticle made of lipid, which has two separate compartments that can be used to encapsulate hydrophilic therapeutic agents, such as doxorubicin, or hydrophobic molecules, such as paclitaxel. The ‘loaded’ liposome can then be targeted to cancer cells in the patient - meaning the drug reaches only the cancer cells, not the surrounding healthy cells.

Another example is the use of iron oxide nanoparticles in neurosurgery, where these are injected into brain tumours to enhance the therapeutic effects of radiotherapy. 

Nanotechnology is also being used to help improve the accuracy of MRI and CT scans. Nanoparticles that emit much more sensitive signals are able to localise deeper into the tissue and help identify tumours and lesions, improving precision of treatment. 

These are just some examples, of course. There is a great variety of applications being explored.

Can you outline a key project you’re working on?

We’re currently working on one which has been running for five or six years, and involves the use of nanoparticles as scavengers for plasma samples that are able to provide a much cleaner and high definition blood proteomic signature. This is tremendously important in the quest for the discovery of new markers in cancer and its various stages.

One of the biggest problems in proteomics biomarker discovery is that the highly abundant proteins that are circulating in our bloodstream are ‘masking’ all the smaller, lower concentration proteins, some of which are secreted by cancer cells or in response to cancer progression.

Due to this masking effect, the identification of smaller and rare proteins is difficult, so we cannot obtain clear and high-resolution proteomic signatures. The idea is that the nanoparticles interact with all of the proteins in the sample - large and small – some of which we know will adsorb onto their surface. 

In this way, we allow also some of the small molecular weight and lower abundant proteins to adhere on the surface of the nanoparticle, avoiding the masking effect, resulting in a much higher definition proteomic signature that isn’t dominated by the larger, highly abundant proteins.  

Sometimes we use the analogy of fishing to explain how this works. When you fish, you can either collect buckets of water hoping you catch some small, rare fish or throw a net and move it around. In the same way, we use the nanoparticles as ‘nanonets’ immersed directly into the bloodstream or into an extracted blood sample and simply allow as many of the proteins to adhere. We then lift the ’nanonets’ and analyse only the proteins that adhered onto them.

Can nanomedicine be used to detect cancer earlier?

Nanotechnology can be used in various ways: by developing sensitive contrast agents for imaging, or to help analyse biological samples more accurately and sensitively, as discussed above. 

All of these technologies can also be used to identify whether a tumour has started building up, dividing, growing or receding. We think that various nanotechnology tools can contribute to the challenge of early cancer detection.

What is the role of graphene in nanomedicine and cancer research?

Identifying biomedical applications for graphene and graphene-related 2D materials is a growing area of nanomedicine research, but clearly at early stages. There have not been any clinical studies using graphene and 2D materials in any oncology setting.

One of the key discoveries in our lab is that macrophages - specialised cells involved in the detection and destruction of bacteria in the body - have an intrinsic affinity to internalise graphene and graphene oxide. When we present graphene oxide flakes into a tissue in vivo, or in cell culture, macrophages are able to very efficiently capture it.

This phenomenon then begs the question: What if therapeutic agents are also attached to graphene, or what if we have some kind of antigen-presenting biomolecules onto the surface?  We are therefore now trying to design such therapeutic strategies and approaches against brain cancer based around this very efficient macrophage internalisation. 

Why has a lot of your research focused on brain cancer?

From our perspective there are two key reasons. Firstly, because traditional systemic immunotherapy is quite poor in this area - it doesn’t work very well, if at all, in most cases of aggressive brain cancers like glioblastomas for a variety of reasons.
Secondly, from the nanoparticle transport and delivery point of view, it is because neurosurgeons offer us a very distinctive target area post-resection where we can deliver the materials directly, and bypass the challenges of crossing the blood-brain barrier.

Our hypothesis is that if we work with this population of macrophages within the tumour, we’ll be able to trigger different types of responses, or enhance the response to radiotherapy, chemotherapy, or immunotherapy. In other words, we can use the macrophage population in brain cancer as a target or an adjuvant to enhance other therapies. 

Graphene can also be used in brain surgery to fabricate a robust, ultra-flexible and highly conductive substrate that can record neural activity. Graphene has a multitude of advantages over traditional metallic materials that are used clinically today, such as platinum or iridium, as it is able to detect very high-resolution electrophysiological signals.

So, working with neuro-oncologists at Salford Royal, we are designing and clinically studying innovative neural recording probes for use in brain cancer resection surgery. These will allow surgeons to clearly differentiate between normal, electrically-active neuronal tissue and cancerous tissue to allow for high-precision surgery with minimal peripheral damage of the healthy brain structures.

How can nano-oncology enhance Manchester’s research ambitions?

Manchester has a unique opportunity in this field because of the breadth, width and quality of expertise between cancer research and physical sciences and engineering of novel materials. It has the capacity to take a new material or technology from a physics lab into the clinic in a very short time, and in the right way. 

While many institutes and centres around the world are exploring the development and application of nanotechnologies, I do believe we have an advantage here, because of the uniqueness of the 2D materials that we are aiming to translate into oncology. 

Another great advantage is that the University is a single large campus institution - it’s much easier to translate something here, compared to other parts of the world. You have the engineering campus next to physics, next to chemistry, next to the medical school, and I think there are very few places around the world that have this seamless connectivity between the different disciplines.

That is, for example, what we are trying to achieve with the graphene neural interface technology I described above. With the funding of the largest-ever research consortium by the European Commission, the Graphene Flagship, we are aiming to start studying clinically the graphene-based neural electrodes developed within the next year with our neurosurgeon colleagues in Manchester. 

On the other hand, I am fully aware that the effort should not be uniquely on graphene - we need to look at other nanomaterials too - not everything needs to revolve around the graphene and 2D materials portfolio. So, it’s a balancing act.

What are your ambitions for nanotechnology research?

I want to see more proof-of-concept, small scale clinical studies on the use of graphene and other advanced materials in nanomedicine and nano-oncology sooner and faster. These will help create knowledge and allow all stakeholders (clinicians, patients, investors, regulators) to feel more confident with the use of such novel materials in the clinic. 

On a broader level, I would like to see Manchester researchers be respected for what we can deliver in this field. I want the University to be securely placed on the map in the niche space of nanotechnology for cancer. I wish people to associate us with excellence, exactly as they connect the Christie Hospital with excellence in oncology patient care. 

I think we already have the respect among researchers globally, but it’s just a matter of maintaining and gaining the reputation. You don’t win anything without persistence and effort. Manchester United needed to be successful consistently for 50 years to build the global reputation and following they enjoy today. We can’t expect to be the Manchester United of nanotechnology (apologies to City fans…) within just a few years!