Is Nanotechnology Ready for Primetime?

0 Journal of the National Cancer Institute , Vol. 98, No. 1, January 4, 2006 - 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 liposomenanoparticle gene therapy designed to home in on and kill cancer cells wherever they are throughout the body. Nanotechnologys 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 nanotechnologys 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 nanotechnologys 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 nmabout the size of a virusand 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 drugs 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 Foundations 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 dendrimerwith folate and a fluorescent protein on either endselectively 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. technology, nanotechnology is becoming big business. Its 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 Womens 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 nanoparticlenucleic 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 Institutes 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 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 concern (...truncated)