AAMC Reporter: October 2009

Nano Comes of Age

What if we could find a way to bypass chemotherapy and deliver cancer drugs directly to cancer cells? What if we could create a better field technique for vaccinating against hepatitis B? What if we could combine new technology with proven drugs to better fight atherosclerosis?

These "what ifs" are all recently published findings from laboratories associated with American medical schools and teaching hospitals. They are specific examples of two areas of research fast coming into their own—nanotechnology and its cousin, nanomedicine.

Researchers debate the semantics, but nanoscale is usually defined as being between one and 100 nanometers. A nanometer is one-billionth of a meter. Nanotechnology can be defined as the understanding and control of matter at this scale. Nanomedicine generally refers to the application of nanotechnology to improving human health.

Perhaps more critical than definitions is the fact that the nanoworld works at the molecular level. The National Cancer Institute reports, for example, that nanoscale devices smaller than 50 nanometers can easily enter most cells. Research at that scale opens boundless new channels to biomedical knowledge.

Already, nano research is showing great promise in cancer treatment. One example comes from Brigham and Women's Hospital and the Harvard-MIT Division of Health Sciences and Technology, where researchers have demonstrated a better way to deliver cancer drugs. They created nanoparticles that pack a double wallop: They can both interfere with pathways that help cancer cells multiply and deliver a higher concentration of cancer drugs to a specific area. Researcher Sudipta Basu, Ph.D., likened the strategy to "shutting the escape route before exposing the cancer to the drugs."

Immunologists at Dartmouth Medical School have used nanoparticles as something of a Trojan horse, designing them to help reprogram cells that ovarian cancers corrupt to feed tumor growth. Cells hit by the nanoparticles switch from supporting the cancer to attacking tumor cells.

Nanotechnology is also opening doors to improved medical imaging. At the Emory-Georgia Tech Nanotechnology Center for Personalized and Predictive Oncology, researchers want to improve the detection of pancreatic cancer, which has a low survival rate because it is usually in advanced stages by the time it is diagnosed. Shuming Nie, Ph.D., and colleagues developed nanoparticles customized with MRI-viewable molecules that attach themselves to pancreatic cancer cells but not to healthy cells. The molecules could help physicians detect pancreatic tumors earlier and could also make related surgery more precise.

Nanomedicine is also aiding the fight against other diseases. Last year, for example, scientists at the Michigan Nanotechnology Institute for Medicine and Biological Sciences at the University of Michigan published results of their work to develop a new, needlefree method of delivering a vaccine for hepatitis B. The new approach combines known hepatitis antigens in a super-fine "nanoemulsion" that allows the treatment to be delivered nasally—and, importantly, without the need for refrigeration in the field.

At the Washington University School of Medicine in St. Louis, researchers are investigating atherosclerosisengineered nanoparticles that combine common statin drugs with fumagillin, which stops blood vessel growth, along with a substance that makes the particles stick in blood vessels. Synergies in the combined treatment point to a potentially better path to control the development of plaques that block arteries.

Medical schools are also experimenting with other applications for nanotechnology. Franklin Tay, D.D.S., at the Medical College of Georgia, is using nanotechnology to try to extend the life of dental fillings. Tay is experimenting with a process that will grow tiny mineral-rich crystals that can be guided into demineralized gaps where fillings bond to teeth.

In the curriculum

Advances in nanotechnology and nanomedicine typically draw on expertise across academic disciplines. Accordingly, many universities have designed academic structures—such as partnerships between engineering schools and medical schools, or interdisciplinary institutes—to support this kind of research. Now, though, the boundaries may be set to blur even further.

In what has been described as a first for medical schools, the University of Texas Health Science Center is creating a department of nanomedicine and biomedical engineering. One result, says Mauro Ferrari, Ph.D., who chairs the new department (he also holds an appointment at the University of Texas M. D. Anderson Cancer Center), is that nanomedicine will now be integrated into the medical school curriculum. Regular workshops and laboratory rotations with a nanomedicine focus are planned.

"Students graduating from our medical school will be fully ready to embrace, understand, and use, rightfully, the new opportunities and new technologies coming forward," Ferrari said.

Regulations lagging behind?

Nanomaterials hold promise in part because they have different properties than their larger counterparts, but those differences also raise safety concerns. While many products on today's market—from tennis racquets to cosmetics—include nanomaterials, some observers say that we don't yet know enough about the possible dangers of such materials. From the Environmental Protection Agency to the National Institutes of Health (NIH) to the Food and Drug Administration (FDA), nano safety is very much on the radar of federal agencies, but to date little work has been done to study potential nano hazards. Some critics say that nanorelated regulation is lagging advances in nano science.

All science and medicine carries risk, Ferrari observed. "To ask if nanotechnology is safe is no different from asking whether organic chemistry is safe. The answer is that some is and some isn't, depending on how you use it and what you use it for," he said. "Given the very tight and effective regulations that FDA has in place and the high level of scrutiny that is exercised, I am not concerned about adverse environmental impacts from nanomedicines," Ferrari said, adding "The FDA has done a great job in being very proactive in asking questions and catalyzing conversations to get scientists to think about things they otherwise would not have thought of."

All of the products that the FDA regulates have the potential to include some form of nanomaterial, said Norris E. Alderson, Ph.D., FDA's associate commissioner for science. One of the regulatory challenges, Alderson said, is that no standard processes exist for the development of nanomaterials, nor standardized means of characterizing them in the context of safety studies. The lack of such basic information makes it difficult "to interpret the data from one study to the next," Alderson said. "That's a major concern for us, and reflects the immaturity of the science related to nanoscale materials today."

"We need the standardization community to come up with standardized procedures and metrology relative to" nanoscale materials, Alderson said.

Asked about those who argue that developments in nano science are getting ahead of regulation, Alderson responded with a question of his own: "Do we just stop developing these products and wait until somebody decides that we know enough that we can go ahead? I don't think that serves the scientific community well either."

The FDA's approach, Alderson said, is driven by the goal of "doing everything we can within the science of what we know about these materials to assure they're safe." As for testing methodologies, he said, "we have seen nothing that would tell us that [FDA] safety testing approaches are not appropriate for nanoscale material." At the same time, he said, the agency would readily amend its assessment procedures if the science behind nanomaterials argues for that.

The FDA is one of many participants in the government's National Nanotechnology Initiative (NNI), which was started in 2001 to coordinate federal nanotechnology research and development. NNI membership includes 25 government departments and agencies, ranging from the State Department to the Forestry Service to the NIH. According to the NNI, federal funding for nanotechnology increased from some $464 million in 2001 to nearly $1.5 billion for fiscal 2009. Funding comes not from the NNI per se, but through individual agencies.

Nano at NIH

Catherine Lewis, Ph.D., director of the division of cell biology and biophysics at the National Institute of General Medical Sciences, co-chairs the Trans-NIH Nanotechnology Task Force, which works to coordinate NIH's overall work in nanotechnology and nanomedicine.

"There's a real recognition that this is an interesting area that needs a lot of development and attention," she said. NIH's commitment to nano research now totals some $300 million, Lewis said, up from $40 million in 2000. Federal funds from the American Recovery and Reinvestment Act could boost those totals, she said, but that effect has not yet been tallied.

As the centerpiece of its Nanomedicine Roadmap Initiative, for example, NIH supports eight Nanomedicine Development Centers. The centers serve as intellectual and technological hubs for interdisciplinary work to develop a high level of understanding of systems within cells. The ultimate goal is to be able to engineer and control those systems to improve human health.

"Being able to work at the nanoscale is a whole new step for biology," Lewis said. In that regard, she said, the NIH is "trying very hard to do as thorough and careful a job as we can to develop better tools to use at the nano level for early diagnosis [of disease] and to develop better therapeutic agents."

Given nano's promise—and the sense that scientists have perhaps plumbed just the beginning of what may be possible—it is clear that this area will be a substantial focus of biomedical research in the years to come.

—By Stephen Pelletier, special to the Reporter