MEDICAL DEVICE INNOVATION - Medical Device Daily

MEDICAL DEVICE INNOVATION 2010
Nanotech experts take aim at
the real cancer killer: metastases
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By LYNN YOFFEE
Medical Device Daily Staff Writer
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-repetitionrate
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.
(This story originally appeared in the Nov.25, 2009 edition
of Medical Device Daily.)
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