Precision Pays Off: How Nanotechnology Promises to Improve Cancer Tests

Chemical engineer Paula Mendes talks to Adam Duckett about her big ambitions for tiny tech

IF PAULA MENDES achieves her goals, her nanotechnology innovations will soon allow doctors to diagnose cancer with greater accuracy, she will improve the production of excessively expensive treatments, and one day, maybe, modify surfaces so they thwart bacteria and eliminate fouling. It’s a fascinating mix, and it all relies on the precision engineering of surfaces at the molecular scale.

Mendes is professor of advanced materials and nanotechnology in the school of chemical engineering at the University of Birmingham. I had naively asked if I could visit the lab to see what her 16-strong team of researchers is working on but of course it’s nanotechnology – there’s nothing she could show me that can be seen with the human eye. So, we settled for a Teams chat instead.

“Nanotechnology is the capability of manipulating or constructing something at a very small scale,” she explains. “What we define as nanoscale is between one and 100 nanometres.”

Characterisation is important too. Mendes and her team must use techniques including atomic force microscopy and X-ray photoelectron spectroscopy to check they have made what they intended. A key challenge with this molecular engineering, as she describes it, is reproducibility. Consistency is crucial because the same material at 10 nm will have different properties when it measures 50 nm.

Mendes’ dedication to such high precision looks set to pay off with the coming launch of a new cancer diagnosis tool currently going through clinical testing. But first, how did she reach this point?

Searching for the best solution

“I studied chemical engineering at the University of Porto in Portugal. I always like the application of things.”

But when Mendes went to work in the textiles industry, she was put off by the urgency to find quick fixes.

“I started thinking maybe I want space to think about the problem and have the time to find the best solution. This is what brought me back to research.”

Mendes undertook a doctorate looking at the process engineering challenges of paper manufacture, which involved studying in Portugal and the UK.

“I finished my PhD in 2002 and asked what should I do next? And this is where nanotechnology comes along. At that point nanotechnology was a buzzword and quite an exciting area. I wanted to be part of that. Sometimes you feel there is a lot that you can contribute [to a new field] instead of being in an overloaded area where a lot of people are already working.”

She studied a postdoc at the University of Birmingham, learning how to modify surfaces for a project creating semiconductor sensors. And then to UCLA in the US where she worked with Fraser Stoddart who went on to win the 2016 Nobel Prize in chemistry for his work creating molecular machines.

“It was a very exciting area of research, and I learned a lot from the group.” However, Mendes says the US was too far from Portugal, so she returned to Europe and decided to steer her research into the biomedical area of nanotechnology. “I thought this is where I can make a difference.”

The team engineered a nanoscale mould whose shape was tailored specifically to the 3D structure of the molecule they wanted to detect. Imagine a nanoscale lock designed to accept only one key – the specific molecular marker that signals disease

Improving cancer diagnosis

In 2020, Mendes and chemical engineering colleagues at Birmingham published research in Advanced Functional Materials (doi.org/n9n8) announcing they had created a super-selective surface that binds only with its target molecule. In essence, the team engineered a nanoscale mould whose shape was tailored specifically to the 3D structure of the molecule they wanted to detect. Imagine a nanoscale lock designed to accept only one key – the specific molecular marker that signals disease.

Mendes has used this technology to create nanoparticles for a new prostate cancer diagnosis tool that could replace the unreliable test that patients currently rely on. The blood test in use today detects levels of prostate-specific antigen (PSA), a protein whose levels can indicate a patient has cancer. However, the tests produce false positives. The UK’s National Institute for Health and Care Excellence (NICE) reports that 75% of men with raised PSA levels have a prostate biopsy that comes back negative – they don’t have cancer.

“This can lead to infection and of course all the stress associated with that process,” Mendes says.

Unfortunately, the test also suffers from false negatives. NICE reports that around 15% of people with normal PSA levels may have prostate cancer.

Many men are told that they are fine but later find out that they have prostate cancer in an advanced stage.

“Our test is completely changing that situation…we want to get rid of all the false negatives and the false positives.”

While the test used today measures for all 56 forms of the PSA protein, Mendes and her team have designed nanoparticles that bind only to the handful of variants that indicate aggressive prostate cancer.

“We aim for a test that will tell if a man has prostate cancer and then he can go for further evaluation in a clinic. It is the first step on the clinical pathway but much more accurate than what we have at the moment.”

Asked about the engineering hurdles faced in developing the technology, Mendes says it originally relied on the optical technique called surface plasmon resonance to detect whether the target molecule had been caught on their nanoengineered surface. When the team started exploring the commercialisation of the technology, they discovered that clinics don’t have access to this equipment. So, they adapted the technology into nanoparticles that can be used in the ELISA assay tests commonly used in labs. Their test fluoresces – it emits light – once those specific alarming molecules are detected.

The genesis of that 2020 breakthrough began eight years earlier. It appears that Mendes’ deliberative search for the right solution, not the quick solution, is paying off.

“Sometimes people say nothing can be perfect, but we need to be as perfect as we can,” she says. “Hard work pays off.”

Clinical tests underway

The system is now fully engineered and going through clinical tests which Mendes expects will be completed by the end of this year. The team is creating a company to commercialise the technology and working with a leading diagnostic firm that plans to license it.

“Maybe in four or five years’ time we should be able to commercialise the technology.”

It’s Mendes’ first spinout. She expects the company will be called Nanoglytek but doesn’t have a name for the product yet.

“We’ll bring patients together to come up with a name for our product. We need something that is for men, and we want to hear their views. So, all these little steps are new but exciting.”

EPSRC and Prostate Cancer UK have helped fund the research. The team is also conducting research for detecting ovarian cancer, but this is less further along.

I ask what she hopes the technology will achieve. A broad smile crosses her face. She says she wants to help change people’s lives.

“It’s the best reward you can have in your career.”

And then her smile fades for a beat.

“I’ve been receiving a lot of emails from patients that have prostate cancer who would like to have the test.” Men, she says, who want to use her test to rule out a false positive or to find out whether they have an aggressive form of cancer. “We’d love to do everything very quickly, but research takes time, and we need to be very thorough.”

Improving drug manufacture

Mendes and her team are also developing nanoengineered sensors that promise to improve the manufacture of novel and very expensive treatments which use extracted human cells. These cell-based therapies have been approved for the treatment of a host of diseases including blood cancers, diabetes, and sickle cell anaemia.

“Cell therapeutics are making a huge difference…so this is an amazing way of treating disease at the moment, but they are very, very, very expensive,” Mendes says.

A study published last year (doi.org/n9q5) found that the median cost of treating more than 100 blood cancer patients with the cell-based therapy Kymriah was US$615,845.

“They are so costly and that means that not everyone will have access to these type of therapies.”

The manufacture of cell-based therapies involves collecting cells from the patient, for example white blood cells in the case of Kymriah, genetically modifying them, and then growing them in bioreactors to increase the number. They are then tested against regulatory-defined critical quality attributes and then infused into the patient.

Mendes is aiming to improve the efficiency of the growth stage. Presently, she says, there is no method for real-time monitoring of the conditions in the bioreactor that indicate the health of the cells. You can test for pH, temperature, and glucose levels but this doesn’t tell you what you need to know.

“When you are growing these cells, you are talking about detecting different types of growth factors that are released by the cells or that we need to add to make sure that the cells are growing healthy and at a good rate.”

To analyse these growth factors today, manufacturers must open the bioreactor and take a sample to go get tested.

“In many cases this leads to contamination, making the cells unusable and forcing the process to start again. It’s very expensive. And, of course, what you have is a patient in need of those cells.”

Mendes has just taken on a new PhD candidate who is working on a project to create nanoengineered biosensors that can be added to bioreactors to detect these specific growth factors. These sensors will be activated remotely by inducing an electrical potential. In simple terms, the signal causes the sensor to activate by changing shape, much like splaying your fingers so you can put your hand in a glove.

“What we have now is a capability to switch on and off the binding site so we can detect specific growth factors at will.”

By adding various sensor arrays into the bioreactor and activating them at different times, Mendes will give manufacturers the capability to monitor these key indicators throughout the production cycle without having to open the reactor. This would help avoid contamination and costly wasted batches, allowing manufacturers to add more growth factors as needed and create fully closed production cycles for both monitoring and tweaking production.

The research is being conducted in partnership with Belgian nano electronics firm Imec R&D, and she expects the technology could be commercialised within five years.

“If we can start to monitor these cells, grow them in the high numbers with the right process, we can bring down this cost. We’ll make these type of treatments available to a wider number of patients. Not just the ones who can afford it.”

I ask what she hopes the technology will achieve. A broad smile crosses her face. She says she wants to help change people’s lives. “It’s the best reward you can have in your career.”

Beating barnacles?

We end the interview talking about what other applications these switchable surface technologies could lead to in the future.

“For a long time, I have been interested in preventing fouling.”

Mendes is talking about the biofilms that form when the likes of bacteria attach to surfaces. It’s a huge challenge for industries to manage as fouling clogs equipment, reduces the efficiency of unit operations like cooling, and causes contamination in food production.

Back in 2012 she developed surfaces that, once activated, prevented bacteria from attaching for half an hour. That’s not great she says, but there’s potential there. She’s now working with microbiologists to understand how vibrations deter bacteria from clinging to surfaces.

If the mechanism can be understood, Mendes imagines we could one day modify surfaces at the nanoscale, so they become activated by natural background vibrations to prevent fouling. This could be background vibrations in a hospital that prevent bacteria from clinging to the modified surface of a catheter to help reduce the risk of infections. Or vibrations in the sea that prevent barnacles from clinging to the modified hulls of ships, reducing drag and improving fuel consumption.

“There is stimulus everywhere that we could use,” she says. Tapping her head, Mendes adds: “It’s a little idea in here. It’s possible one day this will happen. It would be amazing [to develop] but I don’t know if it will be me.”