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21st Century Medicine—Synthetically Engineered Cancer Biomarkers (video)

At this year’s Prostate Cancer Foundation’s 20th annual scientific retreat, attendees were dazzled by research out of MIT that uses nanoparticles for early cancer detection and monitoring as well as sussing out tiny blood clots in the body.

Listen as Dr. Bhatia gives an overview of one aspect of her work to eradicate cancer using cooperative nanosystems:

October 24, 2013 -- Dr. Bhatia is the director of the Laboratory for Multiscale Regenerative Technologies at MIT. She is a member of MIT’s David H. Koch Institute for Integrative Cancer Research, and a Howard Hughes Medical Institute Investigator. Among other aims of her laboratory is the determination “to design multifunctional nanoparticles for cancer applications.” Bhatia and her lab staff are committed to designing nanoparticles and nanomaterials “that can be designed to perform complex tasks such as home to a tumor, sense changes in cells and tissues, enhance imaging, and trigger the release of a therapeutic payload,” says Bhatia on her MIT lab home page.

Today, at the 20th Annual Prostate Cancer Foundation Scientific Retreat in Maryland, Bhatia shared some of her recent work that advances her anti-cancer goals.

Engineering synthetic biomarkers for early cancer detection and monitoring

In a paper published in the journal Nature Biotechnology this year, Bhatia and colleagues describe how they cleverly amplified cancer biomarkers that are normally too scant to be detected via normal blood or urine testing. The researchers decorated nanoparticles with myriads of short fragments of proteins called peptides that are sensitive to being degraded by enzymes called proteases that are produced in great abundance by cancer cells. (These enzymes are the cancer biomarkers.) The injected nanoparticles preferentially home to tumor sites via abnormally leaky blood vessels in the tumor microenvironment. Once the peptide-decorated nanoparticles arrive at the tumor they are quickly swarmed by the proteases that gnaw at the peptides, cutting them into tiny fragments that are then released en masse into the bloodstream. Ultimately these chewed up protein fragments are cleared from the body in urine.

It is then easy to test urine for the amount of peptide fragments present in urine. The amount and type of peptide detected can tell researchers if cancer or disease is likely present in the body. In their study, the researchers tested the synthetic nanoparticles in mice and found they accurately reported early stage colorectal cancer.

bhatia nanoparticles
This image shows Bhatia’s nanoparticles (green) that have accumulated in a tumor of a mouse. Once in the tumor, protease enzymes get to work, gnawing and chewing off the peptide fragments attached to the nanoparticles. Ultimately the peptide fragments are excreted in urine, where they act as reporters on the presence of a cancer in the body.

Bhatia said that after speaking with an eminent prostate cancer researcher regarding the need to better differentiate between aggressive forms of prostate cancer and indolent, non-lethal forms of the disease, she is looking forward to doing research into whether or not invasive prostate cancers exhibit greater proteolytic activity (have higher levels of protease enzyme activity) compared to indolent tumors. If so, this could conceivably improve urine testing to sort prostate cancers by their level of aggression, and help lower overtreatment of indolent tumors as well as undertreatment of aggressive cancers.

Many other disease states have abnormally high levels of protease activity, including diseases associated with inflammation, such as heart disease or liver fibrosis. This technology has the potential to not only aid in early detection, but to enable significant health care dollar savings. For example, due to shifting demographics and increasing rates of childhood obesity, current estimates of children with fatty liver disease caused by obesity range from 9% to 13% of the US population. The gold-standard for diagnosis of certain obesity-related liver conditions is biopsy, and repeated biopsies are often needed for disease monitoring. In her Nature Biotechnology paper, Bhatia et al showed that their synthetic nanoparticles were able to non-invasively monitor liver fibrosis in mice via this urine testing method.

A synthetic biomarker for better detection of blood clots

In a study just published online last month in the journal ACS Nano, Bhatia and colleagues have shown that by modifying their synthetic nanoparticles used to detect cancers and other diseases in mice (described above) they can detect blood clots in mice.

Again using a simple urine test, the researchers show that they can use engineered nanoparticles as biomarkers that report on developing blood clots. While the ability to clot blood is integral to our survival—think of a paper cut that quickly stops bleeding because of our bodies’ ability to clot blood—in many cases blood clots that form inside our bodies can be life threatening, as in the case of heart attacks or stroke. And for cancer patients who have been bedridden for a period after surgery or during recuperation from other therapies, clots may form in legs or the lungs that have the potential to cause death.

Being able to inexpensively and non-invasively monitor such patients for developing blood clots from home after discharge or during a hospital stay might save lives and precious health care dollar resources.

To adapt their nanoparticles to this task, Bhatia et al used nanoparticles decorated with peptides that interact with an enzyme involved in final phase of forming blood clots—thrombin. When the nanoparticles were injected into mice with blood clots in their lungs, the thrombin on the blood clots cut off the peptides attached to the nanoparticles and those peptide fragments where then excreted into the urine. These thrombin-sensing nanoparticles have the potential to find even tiny blood clots that might be missed by traditional testing. For their base nanoparticle, the researchers use a type already approved by the Food and Drug Administration for human use; this will enhance the likelihood of short bench to clinical trial time frames.

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