The advantages of contrast agents within medical imaging have been recognised for many years; for example, contrast-enhanced ultrasound has long been used to image the blood perfusion of various tissues and to detect and characterise focal lesions in the liver. But cutting-edge research being carried out in California, US, could take what is a familiar technology to a whole new level.

Scientists at Stanford University School of Medicine have been pairing microbubble contrast agents with peptides – molecules made up of a chain of amino acids – to create targeted contrast agents that can latch onto cells associated with cancer, potentially giving doctors a way to identify tumours in their early stages. Microbubble contrast agents are widely used in medicine as a cost-effective technique compared to other imaging modalities.

“If you can modify ultrasound contrast agents on the surface so that they can attack cancer-specific molecular markers expressed on the tumour vasculature, for example by adding small peptides on to the surface of contrast microbubbles, these contrast agents can help to visualise small tumours,” explains Dr Jürgen K Willmann, assistant professor of radiology at Stanford University and principal investigator of the Translational Molecular Imaging Laboratory at Stanford. “We and other scientists work on the synthesis of small peptides that can be attached to the surface of contrast microbubbles to make them recognise the markers of early-stage cancers. This gives us great flexibility as we can modify the peptides to make them attach to different markers that we think are important for early cancer detection.”

These molecular markers of early stage cancer are like ‘red flags’ that indicate angiogenesis, the development of new blood vessels, which is often associated with early tumour growth. Molecules that bind to those markers can be linked to the surface of contrast microbubbles. This causes the contrast agent to accumulate in areas of interest, such as diseased or abnormal tissues.

“Smart contrast agents that accumulate at the sites of developing small tumours and help to make the tumour light up nicely.”

By attaching markers in this way, in the future doctors might be able to visualise tumour activity at the molecular level, potentially allowing them to treat the cancer at a much earlier stage and increasing the patient’s chance of survival as a result.

“With a regular ultrasound we would not see the tumour at its early stage”, explains Willmann. “Now we can make ‘smart contrast agents’ that accumulate at the sites of developing small tumours and help to make the tumour light up nicely. It is about combining safe technology like ultrasound, which has been used successfully in medicine for several decades, with novel contrast agents that help identify early-stage diseases.”

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An important advantage of ultrasound is that the technique does not involve irradiation. “If you use a modality that is not harmful such as ultrasound, you are able to offer patients regular scans over a longer period of time,” he says. “You can do repetitive exams, say every six months in a screening setting, without exposing the patient to ionising irradiation.”

“If you use a modality that is not harmful such as ultrasound, you are able to offer patients regular scans over a longer period of time.”

Brave new world

Targeted contrast-enhanced ultrasound, also called molecular ultrasound imaging, is not yet approved for clinical use; in fact it’s still in preclinical research and development. Nonetheless, Willmann predicts that it will become recognised as a powerful imaging tool for the detection of early stage tumours or even pre-cancerous lesions at the molecular level, and may one day open the door to a brave new world of early cancer detection.

“Another exciting area of research is the combination of molecular imaging and blood-based biomarker development for early cancer detection,” he says. “At the Canary Center at Stanford for Cancer Early Detection, directed by professor Sanjiv Sam Gambhir, novel blood biomarkers of early ovarian, pancreatic, lung and prostate cancer are being discovered and validated to screen patients for early-stage disease. When a blood biomarker or a combination of different markers indicates that a patient may have cancer, novel molecular imaging strategies, also developed in our labs, will help to localise and confirm its presence. Hopefully it will have been diagnosed at a still-curable stage.”

Willmann caveats these predictions by pointing out that a lot of work is required to make them a reality, particularly in regard to extensive safety, pharmacology and toxicology testing before the first clinical trials on humans can be carried out. Nevertheless, the technique has the potential to move molecular ultrasound imaging to the forefront of cancer identification and treatment.