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Is Nanotechnology Ready for Primetime?
In October, the National Cancer Institute made its first nanotechnology research awards worth $33.3 million to
12 research groups and seven hubs.
A month later, at the Molecular Targets
and Cancer Therapeutics meeting in
Philadelphia, a press conference devoted
exclusively to nanotechnology highlighted several experimental studies
using nanoparticles, including a
liposome–nanoparticle gene therapy
designed to home in on and kill cancer
cells wherever they are throughout the
body. Nanotechnology’s potential application to cancer seems to be in the news
almost weekly, with new uses of the
technology for diagnosis and treatment
moving rapidly from the lab toward clinical trials. But along with several promising discoveries have come unanswered
questions about nanotechnology’s safety
for human health and the environment.
Since the discovery of carbon nanotubes and their unusual properties in
1991, the hope for and hype of nanotechnology’s potential to better diagnose
and treat cancer have blossomed. In
September 2004, the NCI initiated a
comprehensive 5-year, $144.3 million
research effort, the Alliance for Nanotechnology in Cancer, to develop and
translate cancer-related nanotechnology
research into clinical practice. Its first
awards were $7 million to the Cancer
Nanotechnology Platform Partnerships
and $26.3 million to seven Centers of
Cancer Nanotechnology Excellence, and
they span a wide range of technologies
and cancer types. Projects funded include developing applications to treat
multidrug-resistant tumors, early cancer
detection using nanoprobes targeted to
angiogenic signatures, DNA-linked dendrimer nanoparticles for diagnosis and
treatment, near-infrared fluorescence
nanoparticles for optical imaging, and
hybrid nanotechnology particles for imaging and treatment of prostate cancer.
Nanotechnology deals with structures
that range from 1 to 100 nm—about the
size of a virus—and derives its name
from the Greek word for “dwarf.” (A
nanometer is a billionth of a meter, or
about 25 millionths of an inch). “Nanotechnology allows us to make materials
that are thousands of times smaller than
the smallest cell in the body,” said James
R. Baker Jr., M.D., professor of biologic
nanotechnology at the University of
Michigan in Ann Arbor. “Because these
materials are so small, they can easily get
inside cells and change how they work.”
Baker is developing nanosized dendrimers, molecules with treelike
branches that can be attached to drugs.
Such nanosized “Trojan horses” are designed to smuggle anticancer drugs into
cells and are expected to increase the
drug’s killing capacity and reduce toxic
side effects, Baker said. There are about
700 products now on the market that use
nanotechnology, from sunscreens to electronics to the first cancer drug, Abraxane
(albumin-bound nanosized particles of
paclitaxel), which was approved last
January in the United States for secondline treatment of metastatic breast cancer.
With the National Science Foundation’s prediction that the market for nanotech products and services will hit $1
trillion by 2015, and the U.S. government
already investing $1 billion a year in the
Photo courtesy of James R. Baker Jr. (design by Paul D. Trombley)
This nanosized dendrimer—with folate and a
fluorescent protein on either end—selectively
targets cancer cells and docks with folate
receptors on the cell surface. It is one of the
many possible ways in which nanotechnology
may someday be applied in cancer.
Journal of the National Cancer Institute, Vol. 98, No. 1, January 4, 2006
technology, nanotechnology is becoming
big business. “It’s the beginning of a tidal
wave of products,” said David Rejeski,
director of the Project on Emerging Nanotechnologies at the Woodrow Wilson
International Center for Scholars.
In November, drug delivery pioneer
Robert Langer, Ph.D., of the Massachusetts Institute of Technology in
Cambridge, Mass.; Omid Farokhzad,
M.D., of Brigham and Women’s Hospital
in Boston; and colleagues presented research at the 13th European Cancer Conference in Paris that showed for the first
time that targeted delivery to the prostate
was possible using nanoparticle–nucleic
acid ligand conjugates. They synthesized
nanoparticles for controlled drug release
using a polymer with a long circulating
half-life to encapsulate docetaxel. They
used stable RNA molecules on the
particle surface to bind to the prostatespecific membrane antigen (PSMA) and
guide the particles to the cancer to deliver the chemotherapy to the cells. “We
anticipate filing an [investigational new
drug application] for clinical trials within
18 months,” Farokhzad said.
While researchers believe that nanotechnology can improve drug delivery
and imaging, concerns are growing and
evidence is accumulating that with the
new technology will come unforeseen
human and environmental health hazards. Some nanotechnology advocates
warn that more human and environmental safety testing must be conducted on
products before they are approved.
“We wholeheartedly agree with
safety concerns,” said Farokhzad. His
team is developing their targeted nanoparticles specifically to bypass the
spleen and liver; their tests have shown
that the nontargeted nanoparticles stick
in the microvasculature of the liver and
spleen, which is undesirable. The final
product, which will be given intravenously, must home in only to the prostate and nowhere else, he added.
One recent study conducted by
the International Life Sciences Institute’s Nanomaterial Toxicity Screening
Working Group, coauthored by
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Andrew Maynard, Ph.D., chief science
advisor for the Project on Emerging
Nanotechnologies, raised several red
flags based on previous health and
safety research and on what is known
about the safety of nanosized particulate matter. Animal studies show that
inhaled or implanted fine particulate
matter can cause an increase in lung
inflammation, oxidative stress, and distant organ involvement and lead to increased cell death and inflammatory
cytokine production.
One of the hallmarks of particles is
that their behavior in the nanorange differs from that when they are larger. For
example, nanosized particles of gold and
carbon may be toxic at the nanoscale,
whereas larger particles of the same materials may not be. Other nanomaterials
being used in research include carbonbased particles called fullerenes, metal
oxide particles, polymer nanoparticles,
and quantum dots. Biological activity of
particles increases as particle size decreases, the ILSI study notes. “There is a
strong likelihood that biological activity
of nanoparticles will depend on physiochemical parameters not routinely considered in toxicity screening studies,”
the study authors wrote. For this reason,
it recommends that physiochemical, in
vitro, and in vivo testing be done on all
nanomaterials before they are used in
drugs and devices.
Few existing nanotoxicology studies
address the effects of nanomaterials in a
variety of organisms and environments,
but what does exist raises concerns
about their safety and toxicity, Maynard
observed. Overall number and surface
area are also important to consider in
addition to size. Exposure through inhalation, skin uptake, ingestion, and injection must be tested, the report concludes.
Coating quantum dots may render them
safer, but more research is need to determine long-term stability of the coatings
in the body and when released into the
environment. Nanoparticles can also
cross the blood–brain barrier, which may
be risky. Methods used to test have varied, leading to different results, which
makes it important to standardize testing; the report suggests ways to standardize screening of nanomaterials.
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Earlier reports and studies also raised
questions about safety. In July 2004, the
United Kingdom’s Royal Society and
Royal Academy of Engineering released
a study detailing gaps in knowledge of
nanotechnology’s impact on
health and the
environment.
A July 2004
study published
in Environmental Health
Perspectives
showed that
buckminsterOmid Farokhzad
fullerenes, or
buckyballs—
one of the most popular nanomaterials—
can have adverse effects on marine
organisms: Oxidative stress was found in
the brains and gills of young largemouth
bass exposed for 48 hours to water containing fullerenes at a concentration
likely to be found in an aquatic environment. However, in October, scientists at
Rice University’s Center for Biological
and Environmental Nanotechnology in
Houston found that water-soluble carbon
nanotubes they are developing are less
toxic to cells than the traditional hollow,
insoluble carbon ones. When nanotubes
and buckyballs were made nontoxic with
minor chemical modifications, cytotoxicity of the new nanotubes occurred at 200
parts per billion, compared with 20 parts
per billion.
The House of Representatives’
Committee on Science held its first
hearing on the environmental and safety
impact on nanotechnology in November,
and the general consensus was that more
strategic research is needed to determine
whether the technology is safe and properly regulated, said Maynard. Rejeski
noted that “there are currently no studies
on exposure and response to engineered
nanomaterials in humans. Nevertheless,
our experience with ultrafine aerosol
particles (smaller than 100 nm) has
shown that inhalation of micro- and nanosized fibers and particles can lead to
increased rates of cancer, lung disease,
and adverse respiratory symptoms.”
Nanometer-diameter particles could
leave the lungs via unconventional
routes and affect other parts of the
body, including the heart, liver, kidneys,
and brain. “Next to nothing is known
about the impact of engineered nanomaterials on these organs … or if ingested
as a food additive or by accident”
said Rejeski. In short, there are more
questions than answers for this technology that is developing faster than policy,
he added.
Rejeski urged that a cooperative international effort be made to develop
priorities, align researchers to address
them, and implement an information
infrastructure to support global collaboration. He also strongly recommended
that a blueprint be developed for future
research, oversight, public education
about nanotech, and emergency plans
related to accidental release of nanomaterials into the environment to
avoid pitfalls of public perception
similar to those seen with genetically
engineered organisms.
It’s also unclear how exactly nanotechnology products will be regulated in
the future. The U.S. Food and Drug
Administration
has noted that
it does not regulate technologies and
maintains in a
statement on
its Web site
that “The process of approval
for nanomateDavid Rejeski
rials will be the
same as that
used for other products making the same
claims.” Although the agency is participating in several nanotech working
groups, including one to identify regulatory challenges, it says that the existing
preclinical tests are adequate; “As new
toxicological risks that derive from
nanomaterials are identified, new tests
will be required.” It does note that new
testing models might be needed and
acknowledges that limited basic publichealth research exists on nanomaterials
and that industry and academia must
plan and conduct research to identify
potential risks and to develop adequate
methods to characterize nanomaterials.
Journal of the National Cancer Institute, Vol. 98, No. 1, January 4, 2006
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The Wilson Center will be releasing
another report in January 2006 that
analyzes U.S. regulatory options
for nanotechnology.
The Environmental Defense Fund
calls nanotechnology a “double-edged
sword” that must be managed closely by
government–industry partnership. The first
inventory of government-funded, health,
safety, and environmental risk–related
research was released on November 29 by
the Wilson Center’s Project on Emerging
Nanotechnologies. Its goal: to help define
where research gaps exist and developing
Journal of the National Cancer Institute, Vol. 98, No. 1, January 4, 2006
a roadmap for future risk-related research.
“The government is in a good position to
fund generic research, and industry can
support specific research,” said Maynard.
“Let’s fill in the gaps.”
—Vicki Brower
© Oxford University Press 2006. DOI: 10.1093/jnci/djj028
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