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Ivkov is investigating the application of hyperthermia – heating tissue to non-ablative temperatures – to help destroy tumours. Mild hyperthermia, heating to around 43 °C, inhibits a cell's ability to repair DNA damage, such as that caused by radiotherapy or chemotherapy. More intense hyperthermia, heating to 43–47 °C, will also cause some cell death via apoptosis. From a physiological standpoint, heating boosts blood flow to the tumour, increasing oxygenation and enhancing the efficacy of radiation. "Depositing heat energy in the tumour is beneficial," Ivkov emphasized. "Heat stress has a fairly significant effect on the biological processes of cells."

Depositing and controlling the heat delivered to a tumour, without overheating surrounding normal tissues, poses a challenge. Techniques such as microwave or laser irradiation, and high-intensity focused ultrasound, are under investigation for raising and maintaining tissue temperature. Another approach is to employ a material that has more efficient coupling with the energy source than surrounding tissue. Such a material will convert applied energy to heat more efficiently and generate significant localized heating. Ivkov is exploiting magnetic nanoparticles (MNPs) to do just that.

The idea is to deliver MNPs to the target – a fundamental problem in itself – and then couple magnetic energy with the nanoparticles to deposit heat inside the tumour. "With the MNPs, we exploit magnetic hysteresis, a well-known property of magnetic systems," Ivkov explained. "When a magnetic material is exposed to an oscillating magnetic field it will generate heat through power loss, this is magnetic hysteresis heating, this is physics."

A significant advantage of this approach is that magnetic fields are not attenuated by tissues and can penetrate deep into the body (in contrast with other nanoparticle-based heating schemes that use near-IR excitation). In addition, MNPs are inherently MRI contrast agents, enabling imaging of their location. Finally, MNPs have been used as clinical contrasts for over a decade, generating considerable knowledge as to their safety.

Nanoparticle targeting

Returning to the aforementioned challenge – nanoparticle targeting. "This has been the focus of much of my research over the past decade," said Ivkov. One option is to deliver the MNPs directly into the tumour. This approach suits cancers where metastasis is not usually the cause of death, but rather the growth of local tumours that cause organ failure, such as glioblastoma, advanced liver cancer or pancreatic cancer.

In certain cases, anatomical targeting is possible. For example, normal liver derives most of its blood supply from the vein while a liver tumour takes blood from the artery. This disconnect is already exploited for preferential delivery of chemotherapy to tumours. "Our idea is to add MNPs to the chemotherapy cocktail and deliver them into the tumour too. Then we will apply heat and enhance the efficacy of the chemotherapy," Ivkov explained. "We've been working on this using mouse models, and my co-PI has developed a tumour model in a rabbit."

While these delivery schemes are fairly straightforward in principle, tumours are not homogeneous and the resulting nanoparticle distribution can be heterogenous and variable. "This is where it gets more technically difficult," noted Ivkov. "How can we control the energy deposition to heat the tumour throughout if the nanoparticles are not evenly distributed?"

Energy deposition can be regulated by controlling the magnetic field amplitude, but the response of MNPs to a magnetic field is a complex physics problem. "My mechanical engineering graduate student has done some mathematical modelling," said Ivkov. "We do believe that if you know the nanoparticle distribution in the tumour, which you can obtain from imaging, then in principle you can use computational models to calculate the magnetic field conditions needed to achieve and sustain a therapeutic temperature for the prescribed period of time."

Another challenge is delivering MNPs systemically to treat metastatic disease. "We have worked with many strategies over the years; one that we continue to develop is to label the MNPs with a molecule that preferentially binds to cancer cells," Ivkov explained. "One obvious way is to use a monoclonal antibody directed at an antigen expressed on cancer cells."

Immunotherapy options

Ivkov is also investigating the impact of injected MNPs on the immune system. "Several years ago, I wondered about the nature of this process," he said. "Nanoparticles in many ways resemble a virus, such as in size and shape. So, if we are injecting material that looks like a virus, are nanoparticles going to be inherently immunogenic, or at least interact strongly with the immune system on some level?"

Such interaction with the immune system could have significant implications. For example, is it then a good idea to use immunocompromised animals for cancer research? Will this provide results that are clinically relevant? And as activation of the immune system plays a key role in disease, is there an opportunity to exploit the immunogenicity of nanoparticles as a potential cancer immunotherapy?

Pointing out that all vertebrates get a fever when they are ill, Ivkov explained that elevated temperature switches on specific components of the immune system. "Maybe we have in our hands a tool that inherently targets the immune system. If we deposit heat into the tumour, we might critically affect some immunologic processes that we could turn to our advantage to enhance standard cancer therapy," he suggested. "Perhaps we can target the tumour immune microenvironment and disable or critically affect the immune components that are critical to sustaining that tumour."

Convergent science

Ivkov emphasized that multidisciplinary collaboration has been a key enabler for this complex research project. He added that his experience in working across the fields is also an advantage in his role as Editor-in-chief of CSPO.

"In order to do the type of research I've been doing I've had to become interdisciplinary," he said. "One cannot do this kind of convergent science and still remain a specialist in one area. I believe it is not possible to do this without stepping back and becoming more of a generalist."

He noted that one factor inhibiting the progress of cancer research is that people are accustomed to thinking in specialized terms, while cancer is an exceptionally complex problem. Many researchers are hesitant to step out of their own disciplinary silos, but it's important for everyone to learn more about other disciplines. There are systemic barriers to deal with too: "the theoretical physicist is not going to easily get a grant to fund a project in cancer biology," Ivkov explained. "It's a challenge, the system does not necessarily reward people who have not demonstrated expertise in a particular speciality."

Attempting to shift this mindset, CSPO provides a dedicated home for publishing interdisciplinary research. "I was invited to be on the editorial board at the very beginning and I was excited about the journal," Ivkov told medicalphysicsweb. "I think the concept is timely, it is absolutely the right way to go. The biology and immunology of cancer is exquisitely complex and consequently we're going to need to develop some sophisticated technologies to address it."

Researchers are, of course, already working on this. "The entire field of radiation oncology, for example, is a marriage of physics and biology to treat cancer," said Ivkov. "Developing the technology required the convergence of physics, biology, physiology, mathematics and so on. And even treatment of patients still requires interaction of interdisciplinary teams. I would argue that radiation oncology is an example of successful convergent science to treat cancer."

Looking ahead, Ivkov's plans for CSPO involve increasing the involvement of clinicians, for example using radiation oncology to highlight its relevance to broad audience, including physicians and their patients. His own field of research – cancer nanomedicine – he believes is an area that will attract the interest of a wide community of physicists and biologists. "Nanotechnology is interdisciplinary in nature, and this could provide a useful way to represent the embodiment of convergent science."