Many trace the origins of nanomedicine to a talk Richard Feynman gave at Caltech in 1959—There’s Plenty of Room at the Bottom. During the lecture, Feynman proposed the idea of chemical manipulation at the atomic level and suggested that patients might one day “swallow the surgeon” in the form of tiny machines. Some 50 years later, researchers are still working to realize these dreams, but Feynman would no doubt be impressed by the list of nanomedicine applications being developed today. Nanomaterials have made their way into drug-delivery systems and diagnostics, and are quickly becoming essential basic research tools.
Of course, the reality of nanomedicine doesn’t exactly fit Feynman’s fantasies. The silicon chip boom of the 1980s gave chemists the technology they needed to manipulate substances at the nanoscale. But chemists weren’t necessarily thinking about biomedical applications when they first started working with nanomaterials. “People were playing around with matter partly because they could,” says Paul Alivisatos, a chemist at the University of California, Berkeley, and a pioneer in nanotechnology. One of the most famous discoveries of this exploratory period was the buckyball, a carbon nanoparticle with a unique geodesic-like structure that earned its discoverers the 1996 Nobel Prize in chemistry, even though it wasn’t obvious at the time that there would be any real-world applications for so-called fullerenes. “I think it was a real evolution in the field when it became more clear that there could be a lot of impact in medicine,” says Alivisatos. “Applications emerged in areas people hadn’t anticipated.” Today fullerenes are being developed as drug carriers and for other nanomedicine applications.
From medicine and energy to material science and prevention of bioterrorism, nano-technology developments are occurring at a rate faster than even the field’s most optimistic proponents predicted only a few years ago.
—Jack Uldrich, “Nanotech Needs a Hard Sell, Plus Education” The Scientist, August 30, 2004
Many of the early developments were the products of happenstance. In the mid-1990s, Volkmar Weissig, a pharmacology professor at Midwestern University in Glendale, Arizona, discovered that a well-known compound would self-assemble into 50-nanometer vesicles similar to liposomes (the nanoscale ranges from 1 to 100 nanometers) that could selectively deliver DNA and other cargo across the mitochondrial membrane. “I saw the potential for a mitochondria-targeted nanoparticle, but I thought, ‘Why would anyone want to do that?’ ” he recalls. As a result, he didn’t pursue the project further until he saw, a few years later, that researchers were starting to link multiple diseases to mitochondrial impairments. Today, mitochondria-targeted drugs have become a hot area of pharmacology, and several research groups are now following up on Weissig’s innovation.
Warren Chan, now at the University of Toronto, barely knew what a nanoparticle was when he began his PhD program in 1996. He inherited a project on quantum dots, cadmium-based nanoparticles in the 1- to 6-nanometer range, after his advisor received them in a materials exchange with researchers from another school. Other chemists, including Alivisatos, had been working on quantum dots for use in solar cells, but no one seemed to be exploring their biomedical potential. Chan and Shuming Nie, his advisor at Indiana University, became the first researchers to show that the dots, which emit different colors depending on their size, could be chemically attached to proteins in human cells and were superior to traditional fluorescent probes in many ways. For example, quantum dots fluoresce at least 10 times as brightly as typical fluorescent tags, such as green fluorescent protein, and are significantly less prone to photobleaching, allowing researchers to follow the signal for a longer period of time. The dots can be tuned over a wide spectral range, offering many more color choices than the typical three to five fluorescence probes most often used.
Within two years, the work had led to Chan’s first publication, a 1998 Science paper that has now been cited more than 3,000 times. Today, biomedical researchers can purchase quantum-dot labeling kits from large suppliers, such as Invitrogen. “Now you can find someone working with quantum dots at every major university,” says Chan.
Cancer became the chief disease target for nanomedicine, in part because NIH was investing heavily in the area, but also because it made a lot of sense. With nanoparticles, researchers could attack cancer cells from within—triggering apoptosis by delivering cytotoxins or small interfering RNA—without harming healthy cells as more systemic drug-delivery systems do. Plus, nanoparticles could be engineered to travel through the body without being detected and rejected by the immune system. Heavy metals, such as gold and cadmium, are used to form the backbone of many nanoparticles, and their high surface area-to-volume ratios make it possible to coat them with medicines and other large substrates such as nucleic acids and proteins.
Most of this research has been limited to small animals, but a few therapies have made it into human trials. For example, a gold-based nanoparticle delivery system for tumor necrosis factor-a made by CytImmune, a Maryland-based pharmaceutical company, is now in phase 2 clinical trials. Tumor necrosis factor (TNF) is normally injected in small doses because it is so toxic, but using TNF-coated nanoparticles, researchers can ensure that the drug won’t be released until it exits the leaky vasculature at targeted tumor sites, enabling the use of higher doses. “We really believe that we can get these technologies into the clinic,” says Mauro Ferrari, president of the Methodist Hospital Research Institute in Houston, Texas, who has developed several types of nanomedicine delivery systems. “We work on other diseases, such as diabetes, but about 70 percent of the people in my lab work on ovarian cancer and pancreatic cancer—all the tough stuff. ”
Clinicians are also looking for diagnostic applications of nanoparticles. They want new ways to track tumor progression both in cell culture and in vivo, and surgeons are interested in using quantum dots to label cancers before operating to ensure that they are excising all of the tumor.
Regardless of the application, resolving potential toxicity issues is the next hurdle. Several studies have suggested that nanoparticles are cytotoxic in culture, although animal research indicates the toxicity is less significant in vivo. Chan, who has done a lot of the in vitro work, suspects that the discrepancy is due to the relatively high dose of particles used in cell-culture versus animal models.
Clinicians are also concerned about the long-term effects that the nondegradable metals in nanoparticles could have on the body. Some researchers, including Ferrari, are working on chemically engineering nanomedicines that degrade on their own, but for now, these projects are the exception rather than the rule. “People are just starting to understand how these particles interact with cells and how they might affect human health,” says Chan. “The last five or six years, we’ve had to take a step back from the exploratory side and do some of these basic studies. The same thing goes for nanomaterials manufacturing because now we have to learn how to scale up these technologies.”
Erica Westly is a freelance writer based in New York City.