Nanosensor Technology Detects Ovarian Tumors Smaller than 2 Millimeters

Scientists have developed a highly-sensitive method to detect ovarian tumors composed of nodules smaller than 2 millimeters in diameter in mice, according to a study published in Nature Biomedical Engineering.

In humans, the tumor detection system translates to approximately 5 months earlier than currently possible with existing blood tests.

“What we did in this paper is engineer our sensor to be about 15 minutes better than a previous version, and then compared it against a blood biomarker in a mouse model of ovarian cancer to show that we could beat it,” said senior author Sangeeta Bhatia.

Ovarian cancer is often referred to as a silent killer. Most patients are diagnosed in late stages, and have poor survival rates. If ovarian cancer were to be detected earlier, 5-year survival rates can be more than 90%, according to the study authors.

The novel test employs the use of a synthetic biomarker, a nanoparticle that interacts with tumor proteins to release fragments that can be detected in a patient’s urine sample. Bhatia first reported the use of diagnosing cancer with synthetic biomarkers in 2012, by measuring the activity of endoproteases.

To detect the endoproteases, the investigators designed nanoparticles coated with peptides that can be cleaved by the proteases MMPs to free tiny reporter fragments. The fragments are then filtered out by the kidney and concentrated in the urine. There, they can be detected with various methods, including a simple paper-based test.

In a study published in 2015, the investigators developed a mathematical model of the system to better understand how the particles circulate in the body, how efficiently they encounter the protease, and at what rate the protease cleaves the peptides.

The mathematical model indicated that to detect tumors 5 millimeters in diameter or smaller in humans, the investigators would need to improve the system’s sensitivity by at least one order of magnitude.

For the current study, the investigators used 2 new strategies to boost the sensitivity of their detector. The first strategy involved optimizing the length of the polymer that tethers the peptides to the nanoparticle. Although the reasons are unclear, when the tether is a certain length, specific proteases cleave peptides at a higher rate. Furthermore, the optimization also decreases the amount of background cleavage by a non-target enzyme, according to the authors.

The second strategy involved adding a tumor-penetrating peptide to the nanoparticles, which causes them to accumulate at the tumor in greater numbers, resulting in an increased number of cleaved peptides that are secreted in the urine.

Combining the 2 strategies allowed investigators to heighten the sensitivity of the sensor 15-fold, which was enough to detect ovarian tumors 2 millimeters in diameter in mice. When the approach was tested in the liver, the investigators could detect tumors that originated in the colon.

Although current technology allows physicians to look for a blood biomarker produced by ovarian tumors, the markers do not accumulate in high enough concentrations to be detected until the tumors are 1 centimeter in diameter, approximately 8 to 10 years after they form.

The findings indicated that they could detect disease proteases in microarrays of many tumor cells obtained from different patients with cancer. The authors hope the strategy could eventually be used to help determine which peptides to use for different types of cancer and patients.

“Every patient’s tumor is different, and not every tumor will be amenable to targeting with the same molecule,” Bhatia said. “This is a tool that will help us to exploit the modularity of the technology and personalize formulations.”

Currently, the investigators are further examining whether this approach could be used on other cancers, including prostate cancer.