A Golden Opportunity?

Cancer imaging has been contributing to patient care since X-rays were discovered over a century ago. In its various forms, it impacts almost every aspect of cancer research, diagnosis and treatment (1), so it isn’t hard to understand why we are so eager to update and improve it.

Though we’ve developed a wide variety of imaging techniques – including ultrasound, X-ray computed tomography (CT), magnetic resonance imaging (MRI) and more – these techniques are not without drawbacks. For instance, ultrasound lacks resolution, MRI can’t be used on patients with implanted devices or metal in their bodies, and both X-ray CT scans and newer technologies, like positron emission tomography (PET), involve exposing the patient to radiation.

There’s a clear need to improve cancer imaging, which is what motivated me to develop a new approach that is noninvasive, doesn’t involve radiation and – in my opinion – can accurately visualize cancer and define tumor margins in real-time.

The hybrid approach

Five years ago, it occurred to me that we could combine two separate imaging approaches to create a new methodology – one that could have applications in a clinical setting and even beyond.

The two techniques I combined have been around for years. The first, diffusion reflection, deals with the way a surface reflects light: it can be scattered, absorbed, transferred or reflected. Physicists in the 1980s and 1990s suspected that detecting the intensity of light reflected from tissue would give us information about its properties, but there were simply too many variables; among other things, tissue contains bone and dilated blood vessels that affect light, so detecting a tumor this way is not clinically viable.

The other aspect, nanophotonics, has gained traction in the last 10–20 years. It deals with the behavior of light on a nanometer scale, and is combined with the use of agents – for instance gold nanoparticles – that enhance contrast during medical imaging, so that structures within the body are easier to detect. Conjugating the nanoparticles to anticancer antibodies allows tumor imaging, and this method is already being used in several FDA-approved tests – but it doesn’t work as well in the early stages of cancer, when tumors are too small to be effectively visualized.

To overcome the limitations of each individual technique, my colleagues and I use both – first, we use antibody-conjugated gold nanorods to coat the structure to be imaged, then we use a hyperspectral imaging system to examine the diffusion of light within the tissue. In diffusion reflection, a light source illuminates a sample at a single point on its surface and an array of detectors collects the diffuse light reflected back. In its industrial form, the system is portable, featuring a scanning head with an illumination source and a detector array. With the aid of diffusion reflection, we can detect much lower concentrations of nanoparticles than can be achieved by other methods, down to 0.01 mg/mL – less than one cubic centimeter of tumor tissue.

From modeling to the clinic

Once we’d come up with the idea, the first thing we needed to do was adapt the relevant diffusion equations (2, 3) for a contrast agent like gold and build a mathematical model to correlate our theories with our eventual results. Next, we used imaging phantoms (tissue-like elements designed to behave in the same way as, for example, an arm) to verify that we could detect the gold nanoparticles within living tissues. Third, we conducted in vitro testing on cultured cells, using spectroscopy to determine the tumor specificity of antibody-conjugated gold nanorods (4). Finally, we moved to testing in in vivo models – mice and rats with human-derived head and neck tumors. We injected the rodents with immunotargeted gold nanorods, scanned them with a digital microscope, and performed diffusion reflection measurements to test our technique’s ability to sensitively and specifically detect tumors. In every case, there was a clear distinction between tumor and healthy tissue (5).

Because we now have the ability to deliver high concentrations of gold nanorods specifically to tumor tissue, we’re able to raise the absorption coefficient of the tumor and discriminate quite clearly between healthy and cancerous tissue. With further research, we hope to improve detection and use the technique for determining tumor size as well as presence and location. Meanwhile, we hope to advance our technique to testing for application in the clinic.

Taking a broader view

I feel that this new imaging method can greatly benefit oncologists, but our hope is that it can go far beyond the hospital setting. My dream is for it to be far more widely available – the design is straightforward and fairly cheap, and I would estimate it could be sold commercially for home use at under US$100 a box. With cancers like those of the skin, mouth or throat, the gold doesn’t need to be injected; you could just gargle with the gold solution or spray it onto your skin, then use a home scanning kit to get immediate results. I would like to get the test into many clinical settings, as it’s straightforward and doesn’t require a doctor. For example, individuals at high risk of oral cancer, like tobacco users, could be tested while visiting their dentist – a noninvasive examination with no injection or biopsy – and doing so could potentially catch cancers early and save lives with just a mouthwash and a quick and painless scan.

Whether sold commercially or not, our new method can be added to the pathologist’s current suite of clinical tools. Laboratory professionals will have the option of scanning the suspected area using our system, which will provide them with an additional degree of freedom. This can only work, though, if we overcome our main obstacle – regulatory approval for injecting the gold nanoparticles into the bloodstream. The wheels are turning in the United States to approve this kind of use, but until now, only local injections and sprays have been validated, so the system can detect only surface tumors.

Exploring other avenues

We’re also looking into our system’s potential for applications other than cancer diagnostics. Detecting and characterizing early-stage atherosclerotic vascular injury is a challenge, and we have demonstrated that macrophage cells – which are significant components of unstable, active atherosclerotic plagues – uptake our gold nanoparticles and have a unique diffusion reflection profile (6). In rats, we found that animals with carotid artery injuries were easily distinguishable from healthy ones using our noninvasive imaging method. That project is in its early stages, but we’re working with two groups, one from Germany and one from the UK, who are very interested in developing the technology.

As a researcher and a physicist specializing in nanotechnology and fluorescence imaging, people don’t necessarily expect me to get directly involved in the world of medicine. Now, we’ve joined forces with two medical doctors who are interested in adopting our system and introducing it to their patients. It’s currently being trialed in humans by Michael Wolf at the Sheba Medical Center, Tel Hashomer, and by Avraham Hirshberg at Tel Aviv University, both in Israel. Their efforts in the clinic mean that our test could soon have a meaningful impact on people’s lives, and I find that incredibly exciting.

Dror Fixler is an expert in electro-optics and photonics research, a member of the Nano Photonics Center at the Institute of Nanotechnology and Advanced Materials, and a senior lecturer in the Faculty of Engineering at Bar-Ilan University, Israel.