In a lecture he delivered in 1906, the German physician Paul
Ehrlich coined the term Zuberkugel, or "magic bullet," as shorthand
for a highly targeted medical treatment.
Magic bullets, also called silver bullets, because of the
folkloric belief that only silver bullets can kill supernatural
creatures, remain the goal of drug development efforts today.
A team of scientists at Washington University in St. Louis is
currently working on a magic bullet for cancer, a disease whose
treatments are notoriously indiscriminate and nonspecific. But
their bullets are gold rather than silver. Literally.
The gold bullets are gold nanocages that, when injected,
selectively accumulate in tumors. When the tumors are later bathed
in laser light, the surrounding tissue is barely warmed, but the
nanocages convert light to heat, killing the malignant cells.
In an article just published in the journal Small, the team
describes the successful photothermal treatment of tumors in
mice.
The team includes Younan Xia, Ph.D., the James M. McKelvey
Professor of Biomedical Engineering in the School of Engineering
and Applied Science, Michael J. Welch, Ph.D., professor of
radiology and developmental biology in the School of Medicine,
Jingyi Chen, Ph.D., research assistant professor of biomedical
engineering and Charles Glaus, Ph.D., a postdoctoral research
associate in the Department of Radiology.
"We saw significant changes in tumor metabolism and histology,"
says Welch, "which is remarkable given that the work was
exploratory, the laser 'dose' had not been maximized, and the
tumors were 'passively' rather than 'actively' targeted."
Why the nanocages get hot
The nanocages themselves are harmless. "Gold salts and gold
colloids have been used to treat arthritis for more than 100
years," says Welch. "People know what gold does in the body and
it's inert, so we hope this is going to be a nontoxic
approach."
"The key to photothermal therapy," says Xia, "is the cages'
ability to efficiently absorb light and convert it to heat. "
Suspensions of the gold nanocages, which are roughly the same
size as a virus particle, are not always yellow, as one would
expect, but instead can be any color in the rainbow.
They are colored by something called a surface plasmon
resonance. Some of the electrons in the gold are not anchored to
individual atoms but instead form a free-floating electron gas, Xia
explains. Light falling on these electrons can drive them to
oscillate as one. This collective oscillation, the surface plasmon,
picks a particular wavelength, or color, out of the incident light,
and this determines the color we see.
Medieval artisans made ruby-red stained glass by mixing gold
chloride into molten glass, a process that left tiny gold particles
suspended in the glass, says Xia.
The resonance — and the color — can be tuned over a
wide range of wavelengths by altering the thickness of the cages'
walls. For biomedical applications, Xia's lab tunes the cages to
800 nanometers, a wavelength that falls in a window of tissue
transparency that lies between 750 and 900 nanometers, in the
near-infrared part of the spectrum.
Light in this sweet spot can penetrate as deep as several inches
in the body (either from the skin or the interior of the
gastrointestinal tract or other organ systems).
The conversion of light to heat arises from the same physical
effect as the color. The resonance has two parts. At the resonant
frequency, light is typically both scattered off the cages and
absorbed by them.
By controlling the cages' size, Xia's lab tailors them to
achieve maximum absorption.
Passive targeting
"If we put bare nanoparticles into your body," says Xia,
"proteins would deposit on the particles, and they would be
captured by the immune system and dragged out of the bloodstream
into the liver or spleen."
To prevent this, the lab coated the nanocages with a layer of
PEG, a nontoxic chemical most people have encountered in the form
of the laxatives GoLyTELY or MiraLAX. PEG resists the adsorption of
proteins, in effect disguising the nanoparticles so that the immune
system cannot recognize them.
Instead of being swept from the bloodstream, the disguised
particles circulate long enough to accumulate in tumors.
A growing tumor must develop its own blood supply to prevent its
core from being starved of oxygen and nutrients. But tumor vessels
are as aberrant as tumor cells. They have irregular diameters and
abnormal branching patterns, but most importantly, they have thin,
leaky walls.
The cells that line a tumor's blood vessel, normally packed so
tightly they form a waterproof barrier, are disorganized and
irregularly shaped, and there are gaps between them.
The nanocages infiltrate through those gaps efficiently enough
that they turn the surface of the normally pinkish tumor black.
A trial run
In Welch's lab, mice bearing tumors on both flanks were randomly
divided into two groups. The mice in one group were injected with
the PEG-coated nanocages and those in the other with buffer
solution. Several days later the right tumor of each animal was
exposed to a diode laser for 10 minutes.
The team employed several different noninvasive imaging
techniques to follow the effects of the therapy. (Welch is head of
the oncologic imaging research program at the Siteman Cancer Center
of Washington University School of Medicine and Barnes-Jewish
Hospital and has worked on imaging agents and techniques for many
years.)
During irradiation, thermal images of the mice were made with an
infrared camera. As is true of cells in other animals that
automatically regulate their body temperature, mouse cells function
optimally only if the mouse's body temperature remains between 36.5
and 37.5 degrees Celsius (98 to 101 degrees Fahrenheit).
At temperatures above 42 degrees Celsius (107 degrees
Fahrenheit) the cells begin to die as the proteins whose proper
functioning maintains them begin to unfold.
In the nanocage-injected mice, the skin surface temperature
increased rapidly from 32 degrees Celsius to 54 degrees C (129
degrees F).
In the buffer-injected mice, however, the surface temperature
remained below 37 degrees Celsius (98.6 degrees Fahrenheit).
To see what effect this heating had on the tumors, the mice were
injected with a radioactive tracer incorporated in a molecule
similar to glucose, the main energy source in the body. Positron
emission and computerized tomography (PET and CT) scans were used
to record the concentration of the glucose lookalike in body
tissues; the higher the glucose uptake, the greater the metabolic
activity.
The tumors of nanocage-injected mice were significantly fainter
on the PET scans than those of buffer-injected mice, indicating
that many tumor cells were no longer functioning.
The tumors in the nanocage-treated mice were later found to have
marked histological signs of cellular damage.
Active targeting
The scientists have just received a five-year, $2,129,873 grant
from the National Cancer Institute to continue their work with
photothermal therapy.
Despite their results, Xia is dissatisfied with passive
targeting. Although the tumors took up enough gold nanocages to
give them a black cast, only 6 percent of the injected particles
accumulated at the tumor site.
Xia would like that number to be closer to 40 percent so that
fewer particles would have to be injected. He plans to attach
tailor-made ligands to the nanocages that recognize and lock onto
receptors on the surface of the tumor cells.
In addition to designing nanocages that actively target the
tumor cells, the team is considering loading the hollow particles
with a cancer-fighting drug, so that the tumor would be attacked on
two fronts.
But the important achievement, from the point of view of cancer
patients, is that any nanocage treatment would be narrowly targeted
and thus avoid the side effects patients dread.
The TV and radio character the Lone Ranger used only silver
bullets, allegedly to remind himself that life was precious and not
to be lightly thrown away. If he still rode today, he might
consider swapping silver for gold.
SOURCE