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Ultra-sensitive biosensing technique can spot individual molecules that reveal cancer

BY Jenny Applequist

Despite recent years’ dramatic improvements in cancer treatment, cancer remains second only to heart disease as a leading cause of death for Americans. But a new Nature Communications paper has reported exactly the kind of breakthrough that cancer patients yearn for: development of a highly sensitive new method for performing a liquid biopsy that can identify tiny numbers of individual cancer molecules.

Even better? The method requires only a drop or two of blood from a fingertip, meaning that a simple mail-in home test can take the place of today’s invasive biopsies and draining visits to phlebotomists.

University of Illinois researcher Brian Cunningham (CGD Director/MMG), one of the paper’s authors, explained that for several years, there’s been a focus on a “liquid biopsy” concept whereby one tries to monitor cancer by detecting tumor DNA circulating in the bloodstream. A problem is that circulating tumor DNA gets broken down into small fragments by enzymes in the blood, so that the DNA becomes undetectable.

“So the approach that we’re working on is an alternative that... shows a lot of promise,” he says. “Which is detecting another kind of molecule: microRNA.”

Like DNA, microRNA is a nucleic acid that, for tumors, contains a genomic sequence that originates as part of the genetic alterations that caused and drive the cancer. However, microRNA has a bonus feature: it comes packaged in an exosome, a little blob of material that protects the microRNA from the things in the blood that would otherwise tear it apart. A catch is that only a tiny number of tumor microRNA molecules will make it into the bloodstream.

“So it’s a challenge to have detection sensitivity that’s good enough to be able to see a small number of these very specific microRNA sequences,” says Cunningham, who is a professor and Intel Alumni Endowed Chair in ECE and Bioengineering. “And in the paper, we demonstrate the ability to do that.”

So how do they find the needle in the haystack?

“We’re using light-generating nanoparticles that are called ‘quantum dots’: particles made out of semiconductors that are very small, like five nanometers in diameter... and that’s not much bigger than the size of the molecules themselves that we’re trying to detect,” he says. “We can prepare the quantum dots with nucleic acid molecules that will match and bind with the microRNA molecule that we want to detect, and we can do that in such a way that one quantum dot equals one microRNA molecule.”

They then use a photonic crystal biosensor that amplifies the light from the quantum dots thousands of times over, making it possible to see individual quantum dot + microRNA pairs.

The use of the photonic crystal offers an additional benefit that surprised the team: it greatly suppresses the natural “blinking” of the quantum dots’ light. Quantum dots normally turn on and off at seemingly random times, and indeed are off most of the time. It turned out that the photonic crystal excites the dots such that “they spend the majority of their time on instead of off,” says Cunningham. “They still blink; they still go off sometimes. But they spend most of their time in the on state, which means they’re easier to see.”

New ultra-sensitive biosensing technique can spot individual molecules that reveal cancer

A few years back, co-author Manish Kohli of the Huntsman Cancer Institute was part of a team that identified blood-based miR-375—the type of microRNA used in the present work—as “very specific in advanced metastatic castrate-resistant prostate cancer.” He explains, “It was found that high levels of miR-375 in the blood of [these] patients not only correlated with worse patient outcomes but also predicted that use of a common chemotherapy in advanced prostate cancer, called docetaxel, will not work.”

Kohli says that the present paper is only an early step in an ongoing campaign of ambitious research. The next step will be to figure out how to apply the new methods to advanced prostate cancer patients’ fingerstick blood samples and “what that tells us in terms of the survival of the cancer patient or outcomes of treatments using different drugs.” This work has already been started using cancer patients’ samples.

Cunningham echoes Kohli’s excitement about the work to come. “We just have a wonderful team. This type of research is very multidisciplinary, and we have an excellent team of the clinical and translational researchers at Huntsman, we have people working on new biochemistry methods to do the detection, we have sensor people working on the biosensor and detection instrument; we have Prof. Andrew Smith (CGD), who’s one of the leaders in the world on quantum dots. We have big ambitions... for extending the capabilities of this approach.” He adds that the graduate students and postdocs, led by first author Yanyu Xiong, demonstrated great ingenuity and careful attention to all the detailed methods needed to prove the new physics principles presented in the paper.

One ultimate goal will be to leverage the tests’ ease and precision to understand changes in a patient’s cancer over time, so that treatment can be adjusted accordingly. While something like a CT scan can only provide crude information—say, that a tumor shrank by 20%—a microRNA test could give clinicians more quantitative and precise information about what’s happening with the tumor, so they can make the most appropriate choices among various treatment options. The simple new testing approach should also make it far easier to monitor cancer survivors for signs of returning cancer.

“If successful, this has the potential to be the next generation of liquid biopsies for cancer patients,” concludes Kohli.

The paper is “Photonic crystal enhanced fluorescence emission and blinking suppression for single quantum dot digital resolution biosensing” by Yanyu Xiong, Qinglan Huang, Taylor D. Canady, Priyash Barya, Shengyan Liu, Opeyemi H. Arogundade, Caitlin M. Race, Congnyu Che, Xiaojing Wang, Lifeng Zhou, Xing Wang, Manish Kohli, Andrew M. Smith & Brian T. Cunningham, Nature Communications, vol. 13 (2022),

The project is part of the Center for Genomic Diagnostics, which is an joint activity of the Holonyak Micro & Nanotechnology Lab and the IGB.

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