Vicki Brower- Is Nanotechnology Ready for Primetime?

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Journal of the National Cancer Institute, Vol. 98, No. 1, January 4, 2006 NEWS 9

In October, the National Cancer Insti-

tute made its first nanotechnology re-

search awards worth $33.3 million to

12 research groups and seven hubs.

A month later, at the Molecular Targetsand Cancer Therapeutics meeting in

Philadelphia, a press conference devoted

exclusively to nanotechnology high-

lighted 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 appli-

cation 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 clin-ical trials. But along with several prom-

ising discoveries have come unanswered

questions about nanotechnology’s safety

for human health and the environment.

Since the discovery of carbon nano-

tubes and their unusual properties in

1991, the hope for and hype of nano-

technology’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 Nano-

technology 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 in-

clude developing applications to treat

multidrug-resistant tumors, early cancer 

detection using nanoprobes targeted to

angiogenic signatures, DNA-linked den-drimer nanoparticles for diagnosis and

treatment, near-infrared fluorescence

nanoparticles for optical imaging, and

hybrid nanotechnology particles for im-

aging 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 

Is Nanotechnology Ready for Primetime?about 25 millionths of an inch). “ Nano-

technology 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 biologicnanotechnology 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 den-

drimers, molecules with treelike

 branches that can be attached to drugs.

Such nanosized “Trojan horses” are de-

signed 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 usenanotechnology, from sunscreens to elec-

tronics to the first cancer drug, Abraxane

(albumin-bound nanosized particles of 

 paclitaxel), which was approved last

January in the United States for second-

line treatment of metastatic breast cancer.

With the National Science Founda-

tion’s prediction that the market for nan-

otech products and services will hit $1

trillion by 2015, and the U.S. government

already investing $1 billion a year in the

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 Nano-

technologies at the Woodrow WilsonInternational Center for Scholars.

In November, drug delivery pioneer 

Robert Langer, Ph.D., of the Massa-

chusetts Institute of Technology in

Cambridge, Mass.; Omid Farokhzad,

M.D., of Brigham and Women’s Hospital

in Boston; and colleagues presented re-

search at the 13th European Cancer Con-

ference 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 releaseusing a polymer with a long circulating

half-life to encapsulate docetaxel. They

used stable RNA molecules on the

 particle surface to bind to the prostate-

specific membrane antigen (PSMA) and

guide the particles to the cancer to de-

liver 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 nan-

otechnology 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 haz-

ards. Some nanotechnology advocates

warn that more human and environmen-

tal 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 nano-

 particles specifically to bypass the

spleen and liver; their tests have shownthat the nontargeted nanoparticles stick 

in the microvasculature of the liver and

spleen, which is undesirable. The final

 product, which will be given intrave-

nously, must home in only to the pros-

tate and nowhere else, he added.

One recent study conducted by

the International Life Sciences Insti-

tute’s Nanomaterial Toxicity Screening

Working Group, coauthored by

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.

Photo courtesy of James R. Baker Jr. (design by Paul D. Trombley)

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10 NEWS Journal of the National Cancer Institute, Vol. 98, No. 1, January 4, 2006

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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 nanoma-

terials 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 technol-ogy that is developing faster than policy,

he added.

Rejeski urged that a cooperative in-

ternational effort be made to develop

 priorities, align researchers to address

them, and implement an information

infrastructure to support global collabo-

ration. 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 nano-

materials into the environment to

avoid pitfalls of public perception

similar to those seen with genetically

engineered organisms.

It’s also unclear how exactly nanote-

chnology products will be regulated in

the future. The U.S. Food and Drug

Administration

has noted that

it does not reg-

ulate technolo-

gies and

maintains in astatement on

its Web site

that “The proc-

ess of approval

for nanomate-

rials will be the

same as that

used for other products making the same

claims.” Although the agency is partici-

 pating in several nanotech working

groups, including one to identify regula-

tory challenges, it says that the existing

 preclinical tests are adequate; “As newtoxicological 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 public-

health 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.

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 

nanotechnol-

ogy’s impact on

health and theenvironment.

A July 2004

study published

in Environmen-

tal Health

 Perspectives 

showed that

 buckminster-

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 con-

taining fullerenes at a concentration

likely to be found in an aquatic environ-

ment. 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 withminor chemical modifications, cytotoxic-

ity 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 prop-

erly regulated, said Maynard. Rejeski

noted that “there are currently no studieson 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 na-

nosized fi bers and particles can lead to

increased rates of cancer, lung disease,

and adverse respiratory symptoms.”

 Nanometer-diameter particles could

leave the lungs via unconventional

David Rejeski

Omid Farokhzad

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 particu-

late matter. Animal studies show that

inhaled or implanted fine particulatematter can cause an increase in lung

inflammation, oxidative stress, and dis-

tant organ involvement and lead to in-

creased cell death and inflammatory

cytokine production.

One of the hallmarks of particles is

that their behavior in the nanorange dif-

fers 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 ma-

terials may not be. Other nanomaterials

 being used in research include carbon-

 based particles called fullerenes, metal

oxide particles, polymer nanoparticles,

and quantum dots. Biological activity of 

 particles increases as particle size de-

creases, the ILSI study notes. “There is a

strong likelihood that biological activity

of nanoparticles will depend on physi-

ochemical parameters not routinely con-

sidered in toxicity screening studies,”

the study authors wrote. For this reason,

it recommends that physiochemical, in

vitro, and in vivo testing be done on allnanomaterials 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 inha-

lation, skin uptake, ingestion, and injec-

tion must be tested, the report concludes.

Coating quantum dots may render themsafer, but more research is need to deter-

mine 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 var-

ied, leading to different results, which

makes it important to standardize test-

ing; the report suggests ways to stand-

ardize screening of nanomaterials.

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Journal of the National Cancer Institute, Vol. 98, No. 1, January 4, 2006 NEWS 11

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

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