Every year, about 85,000 Americans are diagnosed with bladder cancer. While treatment is often successful, bladder cancer has one of the highest rates of recurrence of any cancer: Following treatment, about 50 percent of patients develop tumors again within the next five years. This makes it one of the most expensive cancers for society to treat.
MIT researchers have now developed a new way to regularly monitor those patients, which could enable regrowing tumors to be detected much earlier. Using a catheter coated with specialized nanosensors, the team showed that they could detect very low levels of a protein produced by bladder cancer cells and image their location in tissue.
The researchers calculate that this sensing approach is nearly 50,000 times more sensitive than urinalysis, an approach that has been used to monitor bladder cancer in patients. In an animal study, they showed that fluorescent signals produced by the sensors can be used to pinpoint the location of the tumor within the lining of the bladder, providing a chemical image.
"It's like a camera for molecules instead of light," says Michael Strano, the Carbon P. Dubbs Professor of Chemical Engineering at MIT. "If you have a billion nanosensors in an array, you can use them to make a chemical image that helps you locate their source."
Strano is the senior author of the study, which appears today in the journal Nature Nanotechnology . Wonjun Yim, a Schmidt Science postdoc, and Hohyung Kang, an MIT postdoc, are the lead authors of the paper. Other authors include MIT graduate student Marco Machado, undergraduate student Maeve McGinnis, and postdoc Byungha Kang.
"Chemical images"
The new detection approach is based on carbon nanotubes - hollow, nanometer-thick cylinders made of carbon that naturally fluoresce when exposed to laser light. Over the past 10 years, Strano's lab has shown that these nanotubes can be customized to sense different molecules by coating them with "synthetic antibodies" - polymers that can be designed to interact with a specific target.
When the target analytes are present, their interaction with the synthetic antibodies causes the carbon nanotubes to shift the wavelength or change the fluorescent intensity that they produce. Strano's lab has previously developed about two dozen different sensors that can detect different targets, including hydrogen peroxide, riboflavin, and viral proteins .
For the new study, the researchers designed a sensor that could detect a protein known as nuclear matrix protein 22 (NMP-22), which is already FDA-approved for use as a biomarker for bladder cancer. NMP-22 can be detected in urine samples, but it is often significantly diluted, degraded, and cleared after secretion. This means that tumors can only be detected once they have reached more advanced stages.
To enable earlier detection, the MIT team sought a way to deploy their sensors inside the bladder, where they could detect NMP-22 near the tumor at locally elevated concentrations. The device they designed consists of a urinary catheter coated with nanotubes that can sense NMP-22. The catheter also contains a tiny device known as a ball lens, located within the tip of the catheter.
This lens rotates 360 degrees, emitting laser light and then absorbing the fluorescent light emitted by the nanosensors. By analyzing the color and location of these fluorescent signals, the researchers can map the location of any biomarker that is detected.
These chemical images can reveal not only whether the biomarker is present, but also the location of the cancerous cells.
"If you are scanning over a region of tissue, you would like to know not just that there is a signal indicating that a tumor is there, but also its location so that you can treat it or perform a biopsy," Strano says. "Before an early-stage tumor breaks through the urothelium so that it's visible, it's under the surface but still emitting chemical signals that can be imaged. When a chemical hits the catheter, we don't just detect its presence, but we collect a map that pinpoints its location."
Tests in animal bladders showed that this type of detection can be 180 times more sensitive than performing a conventional urinalysis because it detects biomarkers directly where they are produced in the bladder, rather than measuring them later in dilute fluids such as urine, where their concentration is much lower. This high degree of sensitivity would allow the sensors to detect signals from a tumor as small as 16 square millimeters, the researchers say.
Earlier detection
Researchers in Strano's lab are now working on designing a more compact version of their prototype imaging system, so that it could be used more easily at a doctor's office. They also hope to incorporate their sensors into a type of catheter known as a cystoscope, which has a camera attached and is used to visualize tumors in the lining of the bladder.
Currently, patients who have been treated for bladder cancer undergo cystoscopy annually, or in some cases even more often, to monitor for cancer recurrence. The new MIT diagnostics should be able to detect recurring tumors earlier than cystoscopy, making them easier to treat and cutting down on the costs of treatment and monitoring, the researchers say.
"What we're looking for is something that could be faster and more effective. It could be used right in a doctor's office, and it could make that screening more efficient and less invasive, with much lower cost. The goal is to be able to detect potential tumors much earlier," Strano says.
"This paper is exciting because it shows how diagnostics can be more effective when the sensor is brought to the individual," says Daniel Heller, a professor of physiology and pharmacology at Weill Cornell Medicine, who was not involved in the research. "Strano and colleagues demonstrated that a carbon nanotube-based nanosensor technology can be used to monitor a cancer right where it is, improving the speed of cancer detection, and potentially enabling the improvement of cancer treatment."
This approach could also be integrated with endoscopy to detect other types of cancer or other diseases, such as cardiovascular or gastrointestinal diseases, by swapping out the nanosensors attached to the catheter.
"The beauty of polymer chemistry is that if we understand the molecular structures of target biomarkers and the design principles of binding sites, we can develop new sensors tailored to different diseases," Yim says. "You can imagine if these sensors were integrated onto the catheter, they could reveal invisible biomarkers that current endoscopic procedures miss, opening the door to detecting many other diseases in the future."
The research was funded by the Bridge Project of the Koch Institute and Dana-Farber/Harvard Cancer Center, a Schmidt Science Fellowship, the MIT UROP Program, Mathworks Inc., and a National Science Foundation Graduate Research Fellowship.
