Small is big. Although "nanotechnology" has been an academic and media buzz word for several years, the federal government and private investors are now backing a host of initiatives with huge sums.
In fiscal year 2005, federal agencies are slated to spend more than $1 billion on nanotechnologydefined as science and engineering at the scale of one billionth of a meter, or about the width of 10 water molecules. Private concerns are expected to ante up another $5 billion to $6 billion in the United States alone.
Nanotech observers say that the streams of money are flowing from the unique nexus that forms nanoscience, where physics, chemistry, engineering, biology, computer science, and medicine mesh in unexpected ways. At conferences, microchip experts mingle with oncologists, who talk shop with materials engineers and toxicologists. Every corner of science, it seems, is going nano.
"`Interdisciplinary' is so overused, but this is the one field where it truly applies," said Cherry Murray, Ph.D., senior vice president for physical sciences research at Lucent Technologies and Bell Labs, and the organizer of a recent nanotechnology meeting hosted by the National Academies. "We're just learning to talk to each other."
Developing a common language is the goal of the Bush Administration's National Nanotechnology Initiative, a multi-agency umbrella program to build, characterize, and understand nano-scale devices. The NNI lists medicine, manufacturing, materials science, information technology, energy, and environmental science as target beneficiaries.
The program is slated to spend nearly $1 billion in fiscal year 2005, up from $464 million in 2001. The National Science Foundation gets $305 million in 2005, reflecting its broad mission across scientific disciplines. The Department of Defense will spend $276 million, while the Department of Energy gets $211 million. Much of the DOE budget funds five Nanoscale Science Research Centers, which are developing equipment and techniques available to researchers across nanotechnology disciplines.
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The National Institutes of Health, meanwhile, will spend $89 million on nanotechnology in 2005, including nearly $30 million for the National Cancer Institute's new Alliance for Nanotechnology in Cancer, a 5-year program announced in September. "We're talking about devices that can get into cells" to repair DNA, deliver smart-bomb drugs, or highlight a nascent malignancy, explained NCI Deputy Director Anna Barker, Ph.D., at the initiative's unveiling.
Private industry is also rapidly investing in nanoscale science. Investment firms now list nanotechnology indices next to the Dow Jones industrial average and the Nasdaq. Dozens of investment reports have appeared, including the MedMarket Diligence Report, which in January profiled 90 nanomedicine companies, many of them academic spin-offs. Another newsletter, Nanobiotech News, recently listed 35 cancer drugs and diagnostics under development.
Nanomedicine
While the boundaries around "nano" are not completely discretemonoclonal antibodies and other drugs developed with molecular-level engineering are sometimes includedthe first truly nanoscale medicine is already in clinical trials.
Called Abraxane and manufactured by American Pharmaceutical Partners Inc., in Schaumberg, Ill., the treatment is being tested in phase III trials for metastatic breast cancer. Each dose of Abraxane contains billions of nanoparticles coated with paclitaxel (Taxol). By dropping paclitaxel directly into cancer cells, the formulation could potentially eliminate use of toxic solvents that limit the doseand effectivenessof the drug.
"The idea with any nanoscale drug delivery is to land more drug onto the target and less into the surrounding healthy tissue," said Samuel Wickline, M.D., professor of medicine at Washington University School of Medicine in St. Louis.
Abraxane accomplishes this by sneaking paclitaxel through a "trap door" in blood vessels. Patrick Soon-Shiong, M.D., chief executive officer of APP, said that the company chose albumin as the core material for its nanoparticles because cells lining blood vessels are coated with albumin receptors. As an abundant protein in blood plasma, albumin seeps through channels in epithelial cells to thin the blood and lower pressure. Abraxane particles usurp this mechanism and slip through the channels directly to tumor cells below.
In March, APP filed a "fast-track" Food and Drug Administration application for Abraxane based on an ongoing 460-patient phase III trial. The company is hoping to get marketing approval later this year and is developing oral and inhaled versions of the treatment along with the intravenous form now in trials.
Colorful Dots
Although nanoparticles will reach the clinic first as a new way to deliver drugs, many expect similar technology to quickly improve cancer imaging. "Nanoprobes for [diagnosis] are going to have an immediate impact on medicine and oncology," Shuming Nie, Ph.D., director of cancer nanotechnology at Emory University's Winship Cancer Institute in Atlanta, predicted at the National Academies meeting.
In fact, much of the NCI initiative focuses on imaging. One of the first technologies to reach the clinic will be gold particles that can detect 10 or 20 molecules of prostate-specific antigen (PSA), 10,000 times more sensitive than today's PSA tests, said Barker. A single pinpoint of blood will reveal whether a patient needs further testing.
Another technology, "quantum dots," presents a rainbow of potential. Though painstaking to produce, quantum dots are versitile and easy to use, making them attractive for rapid clinical uptake, said Barker. Just a few nanometers in diameter, the dots light up under inexpensive ultraviolet lamps, obviating expensive scanners. Nanodesigners can attach a variety of molecules to the dotsantibodies to recognize telltale cancer proteins, for instancemaking them the "Mr. Potato Head" of medicine, Wickline described. "You can just stick on whatever you need."
In 2001, Nie's group at Emory published an article in Nature Biotechnology describing dots with a cadmium-selenium core and a zinc sulfate shell. The dots possess a curious property seen only at the nanoscale: the color of light they emit depends solely on their size. Dots with a diameter of 2 nanometers emit red, while 6-nanometer dots produce blue. (See News, Vol. 95, No. 7, p. 502.)
After years of painstaking work, the team has improved the dots' design to an incredible degree. Instead of simply emitting one color of light, the fourth-generation dots emit an "optical barcode" that includes various levels of red, green, and blue. "We thought we were making a new discovery, but then we realized that televisions do the same thing," said Nie, referring to TVs and computer monitors that display millions of colors by combining the red, green, and blue in myriad combinations.
The potential applications astound, including the ability to label thousands of genes with individual colors, or tags. Reading and interpreting such rainbows would require sophisticated software, but Nie points to gene microarrays as a model for such data-intensive analysis. "We will be able to look at gene activation at the cellular level in real time," he said.
When tracking tumors, physicians "need quantitative information about protein levels and genes and tumor size," said Wickline. "You want to be able to say, `This tumor decreased by 50%' instead of `This big blob looks less gray.'" Wickline's team is working on nanoparticles that detect nascent capillaries that signal angiogenesis and tumor formation.
But two challenges may hamper quantum dots' utility: their inability to penetrate deep into tissue and their perceived safety problems. If the individual particles remain intact, they present no toxicity issues, according to mouse data from Nie and others. But toxicologists are concerned that the weakly radioactive cadmium ions could somehow break free and damage organs. "To see toxicity, you have to dissolve [the dots]. Our data show that this doesn't happen in the liver or anywhere else," said Nie. "But I don't know if the FDA will buy that." Several groups are working on quantum dots made completely from nontoxic elements, but none have advanced as far as the cadmium dots.
Such early nanodetection, coupled with nanodelivery of drugs that concentrate cancer-killing power while limiting toxicity, could transform oncology. "Everyone wants nanoscale imaging and attomole drug delivery, but it's not easy," said Wickline. "The real test [is] enticing companies to spend the money it takes to bring these things to market."
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