NEW YORK (GenomeWeb) – Researchers at the University of Illinois Urbana-Champaign, the Mayo Clinic, and the Medical College of Wisconsin are developing a diagnostic platform intended for single-molecule imaging of microRNA directly from a single drop of blood.
The technology will be initially applied to metastatic prostate cancer, where fluctuating miRNA levels have been shown to correlate with response to treatment, with a long-term goal of creating a device that can be used by patients for at-home monitoring.
The research team includes engineers at UI and oncologists at Mayo and MCW who were connected through a program designed to encourage collaboration in the development of technology-based healthcare.
The project was recently awarded $1.8 million over five years from the National Cancer Institute. The funded project only aims to develop the core technology, while the at-home monitoring is a long-term goal, said Andrew Smith, an engineer at UIUC, who is spearheading the use of probes for single-molecule imaging.
However, the end goal of at-home liquid biopsy is shaping the diagnostic design from the outset. While nucleic acids can be measured through sequencing, PCR, or microarrays, a test that a patient could use at home would require a minimum volume of blood. At the same time, the system would need to be ultra-sensitive and able to read out many different molecules simultaneously.
MiRNAs are dispersed in blood at a concentration of about several thousand copies in a drop of about 10 microliters in volume. The miRNA-based imaging method the group is developing allows it to measure and count individual molecules in a small volume of sample, which is not something PCR or sequencing can do, Smith said. The project also includes development of a device for at-home blood collection, so that patients can run the test themselves in a manner akin to blood glucose monitoring for type I diabetes, Smith noted.
The system will use complementary nucleic acids and quantum dot and photonic crystals to detect miRNAs, essentially performing an optical amplification. Quantum dots are compact nanoparticles made of semiconductor materials. They have been used for many years for imaging, but have been limited because their relatively large size can impair diffusion. Smith and his colleagues at UIUC pioneered a more compact nanocrystal structure made of layers of different alloys that are brightly fluorescent and developed quantum dots that could be tuned to have equalized fluorescence brightness across a range of colors, providing cleaner imaging.
The photonic crystal element is used to amplify the quantum dot signal by several hundred-fold, Smith said, so that it can be measurable with a low-cost instrument, like a cell phone camera.
Brian Cunningham, also an engineer at UI, will be tasked with adapting the optical imaging technology to a diagnostic platform. Cunningham's work has previously involved developing a smartphone-based biosensor to measure molecules.
Applying the technology to prostate cancer will be based on work by Manish Kohli at the Mayo clinic and Liang Wang at MCW, who showed in a 2014 study that serum miRNA expression patterns could be used to predict early treatment failure in prostate cancer patients.
Specifically, that work demonstrated 34 miRNAs are present in the serum of prostate cancer patients, and altered expression of three of them — miR-103, miR-125b and miR-222 — at the time of radical prostatectomy is prognostic for men at risk of experiencing subsequent early biochemical progression.
Since that publication, Kohli and Wang have also shown that the markers can predict failure for a few different drug treatments for late-stage prostate cancer treatment, Smith said. They also have discovered miRNA biomarkers that can be used to predict prognosis in metastatic kidney cancer.
At the conclusion of the award period, the researchers plan to complete a clinical study, prospectively enrolling and following 100 patients over six days during the course of treatments to measure miRNA concentrations.
A number of other groups have been exploring miRNA biomarkers specifically for prostate cancer. For example, a team of researchers recently discovered an miRNA signature of cancer recurrence after prostatectomy, while a group at Northwestern University has uncovered a set of circulating miRNAs able to distinguish cancer grade, and research at the University of Michigan has linked particular miRNAs to hypoxic prostate cancer cells. According to other research, miRNAs may also be potentially useful to determine patients that may need additional radiation treatment after surgery.
Other researchers are also homing in on methods for miRNA detection direct from patient samples for oncology diagnostics, such as a group in Japan detecting cancer-associate miRNAs in urine using nanowires, or a team at Rockefeller University using multicolor FISH in formalin-fixed, paraffin-embedded biopsy samples.
In order to ultimately commercialize a platform, the Mayo-MCW-UI team expects to either develop a device through a start-up company or license the technology, Smith said. "Both are options; our university loves start-up companies, and we have a wonderful incubating system here for entrepreneurship, so it comes down to how we see the financial structure and what would make it maximally successful," he said.
The Mayo-UI alliance also continues to help clinicians identify needs and bottlenecks and to connect them with engineers able to integrate advanced molecular concepts into clinical scenarios, Smith said. "We see each other a lot, and through meetings and interactions we're able to spawn off these new types of projects really focused on solving clinical problems by applying the most advanced technologies," he said.