Although primary-site cancer can kill people, it's the spread of cancer – metastases – that is most directly responsible for the majority of cancer-related deaths. That's why a team of nanotechnology experts led by University of Arkansas for Medical Sciences (UAMS; Little Rock, Arkansas) researchers have aimed a cocktail of nanoparticles at tumor cells circulating in the blood.

"Most cancer deaths, up to 90%, are related to metastasized tumor cells that spread from the primary tumor to distant organs. Our goal is to provide early diagnosis of metastasis and if successful, prevent, or at least inhibit, this process; and those circulating tumor cells are our target," Vladimir Zharov, director of the Phillips Classic Laser and Nanomedicine Laboratory at UAMS, told Medical Device Daily.

Zharov's team has come up with a relatively straightforward approach to collect, detect and kill those circulating cells: inject a cocktail of magnetic and gold nanoparticles into the bloodstream to target circulating tumor cells. Then a magnet is attached to the skin above peripheral blood vessels to capture these cells labeled by magnetic nanoparticles and a laser then detects of captured cells labeled by gold nanoparticles. The application of two types of nanoparticles with strong magnetic and absorption properties allows for the combination of effective magnetic enrichment of the rare circulating tumor cells with highly sensitive and specific laser-based photoacoustic diagnosis of the accumulated cells. In this application magnetic nanoparticles served as a dual magnetic and photoacoustic contrast agent using the intrinsic near-infrared absorption of an iron core. "These nanoparticles have biological coatings to target tumor cells with specific markers only, and avoid nonspecific binding to normal blood cells, which don't express these markers" he said. "This process of targeting cells in the bloodstream takes a few minutes after injection. Then we attach a magnet to the skin above the vessels and wait, sometimes for 30 minutes to one hour, and then use a near-infrared laser to irradiate vessels near the magnet."

In mice, the approach works. Zharov and colleagues report in Nature Nanotechnology how they have functionalized magnetic nanoparticles to target a marker commonly found in breast cancer cells. Gold-plated carbon nanotubes are also used to improve detection sensitivity and specificity. They are conjugated with folic acid and used as a second contrast agent for photoacoustic detection and photothermal therapy. As a result, the team integrated in vivo multiplex targeting, magnetic enrichment, signal amplification, multicolor recognition and a laser killing circulating tumor cells after their concentration from a large volume of blood in the vessels of tumor-bearing mice.

In a second, related article in Cancer Research, Zharov's team demonstrated that periodic laser irradiation of blood vessels decreases the level of circulating metastatic tumor cells more than 10 times and eventually led to an interruption of metastasis development in distant organs.

"It's a similar procedure, but we use naturally expressed melanin nanoparticles," he said. "We don't need to inject synthetic nanoparticles for this process."

The team developed a method for in vivo photoacoustic blood cancer testing with a high-pulse-repetition-rate diode laser that was applied to melanoma. It uses the overexpression of melanin nanoclusters as intrinsic, spectrally-specific cancer markers and signal amplifiers, providing high photoacoustic contrast of melanoma cells compared with a blood background.

In tumor bearing mice and melanoma-spiked human blood samples, they showed a sensitivity level of 1 CTC/mL with the potential to improve this sensitivity 1,000-fold in humans in vivo, which is impossible with existing assays.

The technique can be used not only for early diagnosis of cancer, but also for laser blood purging of the cancer cells, using noninvasive or hemodialysis-like schematics to prevent metastasis.

Although the group used a melanoma model, "We think our technology is relatively universal because we can inject synthetic nanoparticles specific to each cancer. We just need to develop the nanoparticles with special biological conjugates," Zharov said.

"It's our goal to provide early detection of tumor cells before metastases develops," he said. "Once detected, the second stage is to kill them immediately. The same laser we used for diagnosis can be used for killing the same tumor cells by increasing a little laser energy." This leads to heating of strongly light absorbing nanoparticles accompanied by microbubble formation around overheated nanoparticle clusters on cell membranes that eventually provides cell ablation. The group worked with a customized laser it developed and is now searching for a commercial laser with similar parameters for use in upcoming clinical trials.

Zharov said he has obtained the necessary FDA approvals for pilot clinical study and testing in humans is expected to begin within the next two years.

Lynn Yoffee, 770-361-4789;
lynn.yoffee@ahcmedia.com