Gold nanospheres target and destroy cancer cells
16 February 2009
Hollow gold nanospheres equipped with a targeting peptide find
melanoma cells, penetrate them deeply, and then cook the tumour when
bathed with near-infrared light, a research team led by scientists at
The University of Texas MD Anderson Cancer Center has reported in the
journal Clinical Cancer Research.
"Active targeting of nanoparticles to tumours is the holy grail of
therapeutic nanotechnology for cancer. We're getting closer to that
goal," said senior author Chun Li, PhD, professor in MD Anderson's
Department of Experimental Diagnostic Imaging.
In a promising new application of nanomedicine, when heated with
lasers, the actively targeted hollow gold nanospheres did eight times
more damage to melanoma tumours in mice than did the same nanospheres
that gathered less directly in the tumours.
Lab and mouse model experiments demonstrated the first in vivo active
targeting of gold nanostructures to tumours in conjunction with
photothermal ablation — a minimally invasive treatment that uses heat
generated through absorption of light to destroy target tissue. Tumours
are burned with near-infrared light, which penetrates deeper into tissue
than visible or ultraviolet light.
Photothermal ablation is used to treat some cancers by embedding
optical fibres inside tumours to deliver near-infrared light. Its
efficiency can be greatly improved when a light-absorbing material is
applied to the tumour, Li said. Photothermal ablation has been explored
for melanoma, but because it also hits healthy tissue, dose duration and
volume have been limited.
Lower light dose, great damage
With hollow gold nanospheres inside melanoma cells, photothermal
ablation destroyed tumours in mice with a laser light dose that was 12
percent of the dose required when the nanospheres aren't applied, Li and
colleagues report. Such a low dose is more likely to spare surrounding
tissue.
Injected, untargeted nanoparticles accumulate in tumours because they
are so small that they fit through the larger pores of abnormal blood
vessels that nourish cancer, Li said. This "passive targeting" delivers
a low dose of nanoparticles and concentrates them near the cell's
vasculature.
The researchers packaged hollow, spherical gold nanospheres with a
peptide - a small compound composed of amino acids - that binds to the
melanocortin type 1 receptor, which is overly abundant in melanoma
cells. They first treated melanoma cells in culture and later injected
both targeted and untargeted nanospheres into mice with melanoma, then
applied near-infrared light.
Fluorescent tagging of the targeted nanospheres showed that they were
embedded in cultured melanoma cells, while hollow gold nanospheres
without the targeting peptide were not. The targeted nanospheres were
actively drawn into the cells through the cell membrane.
When the researchers beamed near-infrared light onto treated
cultures, most cells with targeted nanospheres died, and almost all of
those left were irreparably damaged. Only a small fraction of cells
treated with untargeted nanospheres died. Cells treated only with
near-infrared light or only with the nanospheres were undamaged.
An 8-fold increase in tumour destruction
In the mouse model, fluorescent tagging showed that the plain hollow
gold nanospheres only accumulated near the tumour's blood vessels, while
the targeted nanospheres were found throughout the tumour.
"There are many biological barriers to effective use of
nanoparticles, with the liver and spleen being the most important," Li
said. The body directs foreign particles and defective cells to those
organs for destruction.
Most of the targeted nanospheres in the treated mice gathered in the
tumour, with smaller amounts found in the liver and spleen. Most of the
untargeted nanospheres gathered in the spleen, then in the liver and
then the tumour, demonstrating the selectivity and importance of
targeting.
In another group of mice, near-infrared light beamed into tumours
with targeted nanospheres destroyed 66 percent of the tumours, but only
destroyed 7.9 percent of tumours treated with untargeted nanospheres.
The researchers used F-18-labeled glucose to monitor tumour activity
by observing how much glucose it metabolized. This action "lights up"
the tumour for positron emission tomography (PET) imaging. Tumours
treated with targeted shells largely went dark.
"Clinical implications of this approach are not limited to melanoma,"
Li said. "It's also a proof of principle that receptors common to other
cancers can also be targeted by a peptide-guided hollow gold nanosphere.
We've also shown that non-invasive PET can monitor early response to
treatment."
The targeted nanospheres have a number of advantages, said Jin Zhang,
Ph.D., professor in the University of California-Santa Cruz Department
of Chemistry and developer of the hollow nanospheres. Their size — small
even for nanoparticles at 40-50 nanometers in diameter — and spherical
shape allow for greater uptake and cellular penetration. They have
strong, but narrow and tunable ability to absorb light across the
visible and near-infrared spectrum, making them unique from other metal
nanoparticles.
The hollow spheres are pure gold, which has a long history of safe
medical use with few side-effects, Li said.
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