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Nanotechnology and Medicine¹

¹ From the Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 14 Fruit St, MZ-FND 216, Boston, MA 02114. Received October 21, 2003; accepted October 23. Address correspondence to the author (e-mail: thrall.james@mgh.harvard.edu).

Index terms: Perspectives • Radiology and radiologists, research • Technology assessment

Scientific understanding through the millennia has come from studying things first as they present themselves in the natural world and then from studying and understanding their subcomponents at ever smaller scales and finer levels of detail. In physics, this progression of scientific discovery eventually led to the concept of the atom, which was long thought to represent the smallest indivisible particle in nature until the discovery of subatomic particles: electrons, protons, and neutrons. We now know that these subatomic particles are also further divisible into muons, mesons, quarks, and perhaps finally strings (1).

Bioscience has followed a similar reductionist pathway beginning with the empirical study of objects and organisms in their entirety, including human subjects. Scientific study through the years has followed an exponentially declining dimensional scale to organs, tissues, cells, and finally molecules, including DNA and RNA, which hold the molecular basis of life for humans in the form of the genetic code and the mechanisms for its expression. Reflecting this, the contemporary era of medicine is frequently referred to as the "molecular age" of medicine. Molecular biology has become the common pathway for research inquiries that may start out looking quite different at an organ system level.

Medical schools have responded to this scientific reductionism by restructuring and renaming their basic science departments. In the Harvard Medical School, for example, the Departments of Anatomy and Physiology no longer exist, and the Departments of Biochemistry and Pharmacology have been combined into a single Department of Biological Chemistry and Molecular Pharmacology.

Having arrived at a "molecular plateau," the question logically arises about where bioscience will go next. Two directions of study that both rely heavily on the findings in molecular biology are emerging as particularly interesting new opportunities.

First, the emerging discipline of "systems biology" will exploit knowledge of molecular structure to build better understanding of cell function and organ function from the "bottom up" and from the "top down." That is, physiologic processes that were studied historically at progressively smaller scales will now be studied again by starting with their smallest components. In some sense, this represents a "U-turn" in scientific inquiry. It is strongly anticipated that by using information garnered at the molecular level, scientists will achieve improved understanding of function at larger scales than was previously possible. Second, the emerging discipline of "nanotechnology" is another logical outlet for biomedical knowledge at a molecular scale.

Nanotechnology
The prefix "nano" refers to one-billionth. When applied in the metric scale of linear measurements, a nanometer is one-billionth of a meter. The term "nanotechnology" is now commonly used to refer to the creation of new objects with nanoscale dimensions between 1.0 and 100.0 nm (2,3). The term also conceptually implies the ability to manipulate individual atoms or molecules as the building blocks of man-made nanoscale structures (2). The term "nanoscience" is used to refer to research at a nanoscale.

There are many reasons why scientists with diverse interests and backgrounds—including physicists, chemists, engineers, materials scientists, and bioscientists—have converged in their interest to work with and understand things on a nanoscale. In particular, biologic systems are inherently composed of nanoscale building blocks (Table). The width of a DNA molecule is approximately 2.5 nm (4). The dimensions of most proteins are in the range of 1.0 to 15.0 or 20.0 nm, and the width of cell membranes is in the range of 6–10 nm (Table) (4,5). Inherently, most research in molecular biology already takes place on a nanoscale.

Two Nobel Prize–winning discoveries have accelerated interest in nanoscale science. The first discovery was invention of the scanning tunneling microscope in 1981 by Binig and Rohrer (6). This breakthrough instrument, along with a family of derivative devices collectively referred to as scanning probe microscopes, allows the measurement and manipulation of individual atoms on a surface. This in turn made feasible the concept of building from the bottom up, wherein nanoscale structures can be assembled atom by atom into larger and more complex structures. Scanning probe microscopes are being used extensively in bioscientific research.

The second Nobel Prize–winning breakthrough in nanoscience was the discovery of spherical buckminsterfullerenes by Kroto et al in 1985 (7). Fullerenes, or "buckyballs" as they are often called, represent the third allotrope of carbon and are the strongest objects yet known. The other two allotropes are diamond and graphite. The original buckminsterfullerenes were carbon 60 compounds; that is, the compounds contained 60 atoms of carbon arranged in a lattice of hexagonal and pentagonal connections sometimes likened to the surface of a soccer ball. The C₆₀ fullerenes are 1.0 nm in diameter. Some years after the discovery of fullerenes, carbon nanotubes or basically open-ended buckyballs were invented, which led to numerous potential scientific and commercial applications, including novel display units for computers and consumer devices.

Scientists are seeking to exploit unique nanoscale properties to create novel new products and to solve problems of long-standing interest. For example, some nanotubes have superconducting properties that make them attractive for use in new generations of computer systems and electric transmission systems. Nanotechnology is already important in the computer disk industry, where the giant magnetoresistive heads found in all personal computer hard drives have nanoscale structural dimensions to decrease the size required for storing memory bits. The small scale results in a higher density of information that can be stored on a disk of a given size. The consumer arena has not escaped the nanorevolution. Several clothing manufacturers are touting "nanotextiles" that are stain proof and water proof and have wrinkle-resistant properties. The tightly woven materials have nanoscale pores that allow water vapor to escape but are too small for aggregations of water molecules in the form of droplets to enter (Table). Nanoparticle materials are being used to strengthen golf clubs and tennis rackets.

While the full potential of nanotechnology is just now being explored, there are a number of applications that reach into history and prove that new is sometimes old. For example, carbon-based printer’s ink, chemical catalysts, and photographic media all contain nanoparticle components. The role of small size is readily apparent in the case of chemical catalysts, where reactivity is a surface phenomenon. For a given mass of catalytic material, total reactive surface area increases as particle size decreases. The ultimate catalysts in this regard are enzymes, which hold reactive molecules together in precise configurations one by one. Enzyme systems are models for nanotechnology development. The design of novel nanoparticle catalysts has become an important avenue of investigation with worldwide economic and public health impact. Diverse applications include more efficient refining of petroleum and gasification of coal and development of better devices to reduce automobile emissions.

Small scale can also create problems. In nanoscale structures, for example, electrons no longer behave like physical objects that flow in a continuous stream but take on wave mechanical and quantum properties and have the ability to "tunnel" through structures that would ordinarily be insulators. The further development of microchips designed for computers and electronic devices will ultimately come up against this limitation to further miniaturization with conventional designs. Partly for this reason, there is growing interest in the use of biomolecules as components in electric circuits and computing systems to permit further miniaturization, which increases computational capacity. The feasibility of using DNA hybridization to solve complex mathematic problems has been demonstrated at a proof-of-concept level (8,9).

In recognition of the enormous scientific and commercial potential for nanotechnology, President Clinton established the National Nanotechnology Initiative (NNI) in 2000. The NNI encompasses activities of over a dozen federal agencies with a proposed federal fiscal year 2004 budget that approaches one billion dollars (2). The National Science Foundation, the Department of Defense, and the Department of Energy are the three largest funding recipients, with the National Institutes of Health a somewhat distant fourth. The members of the NNI aim to invest their funds in fundamental research.

A number of academic institutions have established special institutes and centers dedicated to nanotechnology. The U.S. Army has established an Institute for Soldier Nanotechnologies by contract with the Massachusetts Institute of Technology that is designed for development of a battle suit to protect soldiers from chemical and ballistic injury.

There has been a proliferation of new journals dedicated to nanotechnology and nanoscience. A journal first called Fullerene Science and Technology and now called Fullerenes, Nanotubes and Carbon Nanostructures is dedicated to the third allotropic form of carbon. Other journals entitled the Journal of Nanoscience and Nanotechnology, the Virtual Journal of Nanoscale Science and Technology, Nanotechnology, and the Journal of Nanoparticle Research are more encompassing; published articles are designed for both biologic and nonbiologic research in nanoscience. The proliferation of these journals is a tangible indicator of the number of scientists worldwide who are interested in nanoscale research. Perusal of the tables of contents of these journals supports the view that nanotechnology is playing an increasing role across a wide array of scientific disciplines.

Medical Applications of Nanotechnology
The National Institutes of Health Bioengineering Consortium, or BECON, held a symposium in 2000 entitled "Nanoscience and Technology: Shaping Biomedical Research" (10). At the conference, eight areas of nanoscience and nanotechnology were addressed that were believed to be most pertinent to research in biomedicine. These areas included synthesis and use of nanostructures, applications of nanotechnology to therapy, biomimetic nanostructures, biologic nanostructures, electronic-biology interface, devices for early detection of disease, tools for the study of single molecules, and nanotechnology and tissue engineering.

The purpose of the conference of the National Institutes of Health Bioengineering Consortium was to foster communication between biomedical scientists and engineers who bring different skill sets and knowledge to bear on these problems and to make the biomedical community more aware of the emerging field of nanotechnology. As presented at the conference and now broadly reinforced by day-to-day experience, there is an increasing ability to manipulate individual molecules at a nanoscale and to combine biomolecules with other nanoscale structures. This ability offers the opportunity for untold new therapeutic and diagnostic applications by enabling the building of novel structures from the bottom up.

In the near term, the most important clinical applications of nanotechnology will likely be in pharmaceutical development. There are already an astonishing number of emerging applications. These applications either take advantage of the unique properties of nanoparticles as drugs or components of drugs per se or are designed for new approaches to controlled release, drug targeting, and salvage of drugs with low bioavailability (11–13).

For example, nanoscale polymer capsules can be designed to break down and release drugs at controlled rates and to allow differential release in certain environments, such as an acid milieu, to promote uptake in tumors versus normal tissues (14). Substantial research is now designed for creating novel polymers and exploring specific drug-polymer combinations (14,15). Nanocapsules can be synthesized directly from monomers or by means of nanodeposition of preformed polymers (15). Nanocapsules have also been formulated from albumin and liposomes. Implantable drug delivery systems that are being developed will make use of nanopores to control drug release.

Drug bioavailability is a related problem with potential nanotechnology solutions. Again, biodegradable polymer capsules show promise. Hydrophobic drugs such as paclitaxel or 5-fluorouracil can be encapsulated in polymers or liposomes with nanoscale cavities that improve drug absorption and bioavailability (16–18). The opportunity exists to systematically look at both successful and failed drugs to see which ones might benefit from novel delivery vehicles. In some cases, reformulation of a drug with smaller particle size may improve oral bioavailability.

An especially pressing problem in bioavailability is cell transfection in DNA gene therapy. Current methods have significant limitations, including the risk of inadvertent transmission of disease by viral vectors. This has led investigators to explore polymer-DNA complexes and liposome-DNA complexes for gene delivery (19). It has also been demonstrated that compacted DNA in the form of nanoparticles can be used to transfect postmitotic cells (20).

In spite of their risk and limitations, viral vectors are an efficient biomimetic approach to drug targeting and delivery. To take advantage of viral transfection efficiency with reduced risk of unwanted sequelae, investigators are exploring the use of viral components. The tat peptide from human immunodeficiency virus (HIV) and other viral proteins are being attached to DNA, proteins, and other materials for uptake into cells. These nanoassemblies mimic the action of the fusion proteins that make viral transfection efficient (21,22).

The quantum properties of nanoparticles have also been exploited in the formulation of drugs. In one commercial over-the-counter sunblock product, zinc oxide is formulated in nanoparticle size. The nanoparticles are too small to interact with the wavelength of visible light (400–900 nm). Thus, the nanoformulation is colorless versus the undesirable white color of conventional zinc oxide sunblock, yet the nanoparticles still block the shorter wavelengths of ultraviolet light.

Fullerenes have captured the imagination of pharmaceutical researchers for a number of their unique properties as drug candidates. In the early 1990s, modified C₆₀ fullerenes were found to have antiprotease activity and were recommended for the treatment of HIV and acquired immunodeficiency symdrome, or AIDS (23,24). C₆₀ fullerenes also have powerful antioxidant properties and are being incorporated into drugs designed for the treatment of neurodegenerative disorders including amyotrophic lateral sclerosis, also known as Lou Gehrig disease, and Parkinson disease.

Researchers take advantage of the fact that C₆₀ fullerenes have 60 potential carbon-binding sites compared with only six on a benzene ring. This offers the opportunity to use fullerenes as scaffolds for complex nanoassemblies. For example, a design might include the attachment of targeting antibodies along with either chemotherapeutic agents or radioactive materials for the treatment of cancer.

C₆₀ fullerenes also have the great advantage of being rigid molecules, unlike many conventional pharmaceuticals that are flexible in solution and lack precise molecular targeting for that reason. Because of this rigidity, fullerenes can be complexed with other molecules by using precise measurements and configurations based on the properties of the target.

Whether or not any fullerene-based pharmaceuticals will find their way into clinical practice is not yet known. Work on them serves to show the potential of the nanotechnology approach to pharmaceutical development, that is, the precise molecular engineering of specifically targeted nanoassemblies with multiple components.

Nanotechnology is being used to create new diagnostic pharmaceuticals for use in medical imaging. The class of compounds known as superparamagnetic iron oxides (SPIOs), also known as monocrystalline iron oxide nanoparticles, or MIONs, have shown promise for a number of magnetic resonance (MR) imaging applications both as naked particles and as magnetic labels (25).

Because of their small size, the SPIO particles are not immediately cleared by the reticuloendotheial system as are larger particles, and they remain in circulation for tens of minutes and even hours in substantial percentage. This permits contrast material–enhanced MR imaging of arteries and veins. More important, the SPIO particles are taken up in lymph nodes throughout the body (26). As reported recently, SPIO-enhanced MR imaging of lymph nodes in patients with prostate cancer resulted in very high sensitivity and specificity values for detection of nodal metastatic disease that were superior to those with existing computed tomographic or MR imaging methods (26). Areas in lymph nodes affected by metastatic tumor tissue have normal lymphatic tissue replaced by tumor tissue, which does not accumulate SPIO contrast material. Affected tissues are characterized by failure of signal dropout on contrast-enhanced T2-weighted MR images.

Cross-linked iron oxides are second generation superparamagnetic compounds (27,28). These nanoscale structures have dendritic arms that readily permit complexing of targeting moieties, such as antibodies or enzyme substrates. The approach is very flexible and allows attachment of other reporter labels, such as fluorescent tags, thereby creating a single contrast agent with both optical and magnetic properties.

Virtually all contrast agents being developed for near-infrared fluorescent optical imaging qualify as nanoassemblies. They typically have a polymer backbone, a receptor-targeting moiety, and a fluorescent reporter label (29,30). Likewise, many agents now being developed for nuclear medicine applications fall into the same construct, with multiple components designed to confer in vivo localization and external detectability.

Bioanalysis is another rapidly advancing area of nanotechnology research that is going in many directions (31). At two ends of the spectrum, scanning probe microscopes permit study of individual molecules, while commercially available nanoscale oligonucleotide arrays for gene expression research now encompass the entire human genome on a single chip (31–33). Scanning probe microscopes are so sensitive that they can detect differences in one base pair in DNA hybridization. This approach eliminates the need for labeling of the DNA strands, which simplifies the process in comparison to that with chip arrays (31,32). The scanning probe microscope method can be applied to proteins and other biomolecules and is being combined with array technology for high-throughput applications.

Nanotechnology is putting the goal of building a "lab-on-a-chip" within reach (7,31). By using very small channels, only nanogram quantities of analytes and reagents are required. Throughput can increase while cost decreases. Such devices could dramatically change the care model by making sophisticated tests widely and immediately available at lower cost in office settings, at home, or at a patient’s bedside.

Nanopore filters show superior performance for many applications in comparison to that with mircropore filters (34). Improved filtration in drug production is designed for better purity, sterility, and apyrogenicity. Selective pore size can be used analytically to separate and identify molecules, and nanofilters offer new approaches to water purification and environmental cleanup that have enormous potential global impact.

Biosensing is closely related to bioanalysis but requires the interfacing of a nanodevice with the patient in some way (31,35–37). One way that has been proposed is the use of nanotubes inserted through the skin to continuously monitor electrolytes or blood glucose levels. A further challenge to making this approach practical is the interface of nanodevices with electronic readout devices.

Implantable prosthetic devices and nanoscaffolds for use in the growing of artificial organs are other goals of nanotechnology researchers. Nanoengineering of hydroxyapatite for bone replacement is reasonably advanced (38,39).

Futurists imagine a world where medical nanodevices are routinely implanted or even injected into the bloodstream to monitor wellness and to automatically participate in the repair of systems that deviate from established norms. These nanobots could be personalized by tailoring them to patient genotype and phenotype to optimize intervention at the earliest time in the course of disease expression.

While medical science is undoubtedly still years away from this futuristic vision, the momentum necessary to fuel progress in nanotechnolgy is definitely present. Financial support for the NNI is growing exponentially, as is private investment (40). Dozens of small start-up companies have been established, and hundreds of patents have been issued. Nanotechnology is already changing how bioscientific research is conducted and how medicine is practiced: Think small.

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