Rarely does a new medical device show promise across broad areas of disease diagnosis and treatment ranging from cancer to cardiovascular disease, stroke and infections. But that is the case with translational research being conducted at the University of Arkansas for Medical Sciences (UAMS) by a team led by Vladimir Zharov, PhD, DSc, director of the Arkansas Nanomedicine Center at UAMS. Zharov and his team of researchers inject a cocktail of magnetic and gold nanoparticles with a special biological coating into the bloodstream to target circulating tumor cells (CTCs). A magnet attached to the skin above peripheral blood vessels can then capture the cells.
“By magnetically collecting most of the tumor cells from blood circulating in vessels throughout the whole body, this new method can potentially increase specificity and sensitivity up to 1,000 times compared to existing technology,” Zharov said. “Once the tumor cells are targeted and captured by the magnet, they can either be microsurgically removed from vessels for further genetic analysis or can be noninvasively eradicated directly in blood vessels by laser irradiation through the skin that is still safe for normal blood cells.”
The clinical prototype device was used in trials involving melanoma and breast cancer.
Zharov said indications are that the device will represent a huge step forward because cancer is most easily and effectively treated if it’s found at a very early stage. Zharov’s team demonstrated that periodic laser irradiation of blood vessels decreases the level of metastatic CTCs more than 10 times and eventually led to an interruption of metastasis development in distant organs. “Further study could determine whether these new cancer treatments are effective enough to be used alone or if they should be used in conjunction with conventional cancer therapy,” Zharov said.
The potential for cancer alone is huge considering the fact that most cancer deaths are the result of metastasis due to the spread of tumor cells from the primary tumor through the blood. But there are also other very promising applications.
“The nanomedicine-based approach to read and treat whole blood in the body with nanotechnology seems to be universal, with further development holding the promise for the diagnosis and treatment of many diseases, including infections or cardiovascular disorders to prevent stroke and heart attack,” said James Suen, MD, chairman of the UAMS Winthrop P. Rockefeller Cancer Institute’s Department of Otolaryngology, Head and Neck Surgery.
The prototype that uses “in vivo flow cytometry” has demonstrated in a pilot clinical trial that it can safely and noninvasively detect melanoma CTCs directly in patients’ blood vessels at sensitivity rates up to 300 times greater than conventional tests of blood drawn from the body. The patient trial was run by Laura Hutchins, MD, a UAMS hematologist and medical oncologist.
A breakthrough using the technology was made by a member of Zharov’s team, Ekaterina Galanzha, MD, PhD, DSc, who demonstrated its ability to label and track individual CTCs as they circulate in the bloodstream. This discovery, using “photoswitchable flow cytometry,” could help shed important new light on the behavior of CTCs.
Galanzha said the research should help fill the gaps in understanding by researchers of the basic mechanisms of CTCs, such as where they’re likely to go, which cell’s behavior contributes to metastasis, and how rapidly cancer cells shed from primary tumors into the bloodstream.
Conducted in collaboration with Albert Einstein College of Medicine in New York and published in Chemistry & Biology, Galanzha’s study focused on CTCs with photoswitchable proteins. This approach was chosen because unique proteins within the individual CTCs reveal themselves when exposed to laser light. When a CTC passes through the laser beam, it changes from green to red.
The red color becomes the CTC’s permanent “label,” enabling researchers to track it as it moves through the body’s blood vessels using the principle of in vivo photoswitchable flow cytometry.
“The cell proteins are genetically encoded, so when the labeled cells invade organs and divide, they get their green color back again,” Galanzha said. “This allows us to distinguish dividing and potentially metastatic cells from dormant cells, which keep their red color. It’s amazing.”
Having the ability to track individual CTCs over time should capture the imaginations of scientists looking to unravel the mysteries of metastatically aggressive cells, Galanzha said.
“Photoswitchable flow cytometry opens the door for a new bio-technical platform for basic research and possible clinical applications,” she said.
For cancers that lack the photoswitchable proteins, Zharov invented artificial photoswitchable nanoparticles to detect and label their CTCs. The final destinations of labeled cells can be tracked and controlled by photoacoustic imaging in Zharov’s laboratory.
Zharov hopes that someday the same device he is using to identify and label CTCs in humans can be recalibrated to kill the cells, making his device a “theranostic” instrument. “Theranostics” refers to procedure with combined diagnostic and therapeutic capabilities.
“That’s our next ultimate goal, to treat patients using our technology,” Zharov said. “It is a single technology that can be used for treatment and for guiding treatment. The same laser can be used to kill the cancer cells. We’ve already demonstrated that in animal models.”
Other members of the team include Dmitry Nedosekin, PhD, a biochemical engineer; Yulian Menyaev, PhD, a biomedical engineer; and Mustafa Sarimollaoglu, PhD, a software specialist. Zharov’s team collaborates productively with other UAMS scientists and departments including Mark Smelters, PhD, Dept. of Microbiology and Immunology; Robert Griffin, PhD, Dept. of Radiation Oncology, and Nancy Rusch, PhD, Dept. of Pharmacology and Toxicology.
Currently several patents are pending on Zharov’s technology, which his team is refining for a more portable device that will offer real-time analysis. Zharov has an agreement with Cyto Wave Technologies, a company that has preliminary plans to bring the commercialized technology specifically for melanoma diagnosis.
Research is currently supported by grants from the National Institutes of Health totaling about $3 million, and the UAMS Translational Research Institute, $50,000.

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Go online to http://cancer.uams.edu/news/?sid=2&nid=10375

Meta tags: University of Arkansas for Medical Sciences, UAMS, nanotechnology, metastatic cancer, breast cancer, melanoma, Cancer Research, Nature Nanotechnology, Vladimir Zharov, Arkansas Nanomedicine Center, magnetic collection of cancer cells, in vivo flow cytometry, James Suen, MD, Laura Hutchins, MD, Becky Gillette, circulating tumor cells, Ekaterina Galanzha, photoswitchable flow cytometry,

Photo notes: Photos sent of Vladimir Zharov in his laboratory.