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 second-line treatment of metastatic breast cancer.
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.
Credit: Photo courtesy of James R. Baker Jr. (design by Paul D. Trombley)
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 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.
David Rejeski
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 prostate-specific 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.
Omid Farokhzad
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 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 carbon-based 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.
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 buckminsterfullerenes, 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 nanomaterials 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 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. 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.”
