Smaller Probes, Earlier Detection

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Gold nanoparticles imaged using electron microscopy and then colorized. They are used in a new test for prostate cancer.

Growing up, I used to watch the G.I. Joe cartoon series. At the end of every episode was a short announcement by a G.I. Joe hero on any number of topics, ranging from avoiding old refrigerators as hiding places to promoting sportsmanship on the athletic field.  Each would end with one of the characters saying, “Now we know!” followed by the G.I. Joe hero with “And knowing is half the battle.”

We throw that phrase around occasionally in my laboratory, where we develop improved diagnostics for diseases like prostate cancer. Determining the disease at hand as early as possible is crucial to positive outcomes for patients. Of course, the other half of the battle is having an effective treatment. Although this piece focuses on the first part of the battle, we are working on the treatment part too.

To arrive at the correct diagnosis, a physician has at his or her disposal a number of tests—imaging tests (i.e. pictures), blood tests, urine tests, psychological tests, etc. A test that involves a fluid sample from the patient is only as good as 1) the chemistry making up the test and 2) the presence or absence of a unique marker of the disease in the specimen being tested. Prostate cancer, which affects one in six men in America, is usually detected by monitoring the blood levels of the protein PSA, or prostate-specific antigen. Elevated levels of PSA indicate a medical problem, ranging from inflammation of the prostate, to an enlarged prostate, to cancer.

Following confirmatory testing, a large number of patients diagnosed with prostate cancer undergo removal of the organ in hopes of being cured. (Learn more about prostate cancer treatment options here). After the prostate has been removed, trace amounts of cancerous cells may remain, either at the surgical site or in areas to which the cancer has already spread (e.g., the lymph nodes). A rising PSA level following surgery can then indicate that the cancer may be returning.

Unfortunately, the sensitivity of current blood tests limits a physician’s ability to monitor rising PSA levels following prostate removal surgery. The test cannot detect PSA levels less than 100 pg/mL, or picograms of PSA protein per milliliter of blood. This is important because nearly every patient who has undergone prostate removal will have an initial PSA concentration well below this number. So, even if a patient’s PSA level is consistently rising, potentially indicating cancer recurrence, the patient and the treating doctor won’t know until the 100 pg/mL limit of detection is surpassed. This means that levels could be rising for months, or even years, before being recognized by the physician.

But what if a more sensitive test could detect lower levels of PSA? Could prostate cancer recurrence be diagnosed earlier? If so, would earlier treatment result in better outcomes for patients? All good questions….

Collaborative work with my laboratory; Chad Mirkin, professor of chemistry at Northwestern; Dr. William Catalona, a prostate cancer surgeon and expert at Northwestern; and biotech company Nanosphere uses recent advances in nanotechnology to improve upon the current PSA test and answer some of these questions. But, before we explore how the new test works, let’s first take a look at how PSA is measured in the current process.

Like many proteins, PSA is detected in the blood by using antibodies.  Antibodies are also proteins, and they’re produced by the immune system to recognize and bind to other specific proteins.

To ensure accuracy, the test actually uses two antibodies—one that binds to PSA initially, and a second that both binds to PSA and brings with it another important molecule. This molecule is often an enzyme, which accelerates a chemical reaction that changes the color of the solution in which detection is taking place. The degree of color change corresponds to the quantity of PSA protein in the blood sample.  The darker the solution, the more PSA it contains.

The new test works in the same basic way, but with a few key differences. (For a visual exploration of the new test, see the "Detecting the Undetectable" slideshow below.) First, the initial antibodies are placed on the surface of micron-sized (slightly smaller than a human cell) magnetic beads. This allows the antibodies to move freely through the solution, actively sampling blood and more efficiently connecting with PSA, rather than remaining on the bottom of a test dish.    

Then, the secondary antibody is secured on the surface of a gold nanoparticle that also carries 200 strands of DNA. These strands replace the enzyme and are ultimately, like the enzyme, responsible for signaling the presence and quantity of PSA present in the sample under scrutiny. Because there are 200 strands of DNA for every one PSA molecule detected by the gold nanoparticle, the signal is highly amplified. These DNA sequences are later released and detected using a color change test that is highly accurate and amplifies the signal further. 

These signal amplifications made possible by nanotechnology make the new test significantly more sensitive—approximately 100 times—allowing us to measure PSA molecules far below the detection limit of predecessor tests. Recent research has demonstrated that, with this increased sensitivity, we might detect prostate cancer recurrence much earlier, follow patients much more closely when they are receiving treatments for advanced disease, and more accurately determine prostate cancer cure at low PSA levels. In collaboration with Dr. Catalona, we are further validating the test in patients who have been treated for prostate cancer at Northwestern Memorial Hospital.

Also exciting is the potential for similar nanotechnology-enhanced tests to revolutionize the way we diagnose many diseases. It may someday be applied to any number of conditions, like ovarian and pancreatic cancer, where early detection could enable substantial improvements in treatment and patient survival.  In short, nanodiagnostics may allow doctors and patients to know months or even years sooner just what they are up against. And knowing is half the battle.

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