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The World of Nanotechnology Max Sherman, RPh Sherman Consulting Services Warsaw, Indiana US Pharm. 2004;12:HS-3-HS-4. There have been many changes in the science of drug discovery in the past decade. One advance that stands out, for example, is employing a patient's genetic profile to judge whether or not a specific drug will be effective in treating disease. Decoding the human genome spawned "pharmacogenomics." This term was applied in the late 1950s, first to understand the genetic differences that cause people to metabolize drugs differently, and then to describe the creation of drugs in the 1990s that are individually designed for a person's genetic makeup. Genetic testing is now used to identify breast cancer patients who might benefit from therapy with Herceptin (trastuzumab), a monoclonal antibody. The drug targets cancer cells that overexpress a protein called HER-2, which is found on the surface of cancer cells. In tumor cells, errors in DNA replication may result in multiple copies of a gene on a single chromosome. This alteration, known as gene amplification, leads to an overexpression of the HER-2 protein, resulting in increased cell division and a higher rate of cell growth. Herceptin is used only to treat cancers that overexpress the HER-2 protein.1 The 21st century will no doubt be witness to a number of new discoveries in this field as scientists continue to solve the riddles of human genomics. Precise genetic testing will be pivotal in employing new monoclonal antibodies and other new drug therapies. The Science of Nanotechnology Science is learning more about the human body on a smaller and smaller scale. The next wave of drug discovery will likely focus on nanotechnology. We will in fact be seeing more and more scientific terms beginning with nano. Nanoscience has been deemed the technology breakthrough of tomorrow, and several research groups are developing programmable implants that could revolutionize the way drugs are made and administered. Nanoparticles could be used to deliver chemotherapeutic agents exactly where they are needed, preventing the side effects that so often result from potent medicines. Artificial nanoscale building blocks may one day be used to help repair tissues such as skin, cartilage, and bone.2 According to one expert in the field, nanomedicine will have extraordinary and far-reaching implications for the medical profession, for the definition of disease, and for the diagnosis and treatment of medical conditions, including aging.3 Before embarking on some of the aspects of nanotechnology it is prudent to include a few definitions. Defining the World of Nanotechnology The prefix nano- is a Greek term meaning one billionth. One nanometer (abbreviated as 1 nm) is 1/1,000,000,000 of a meter. To get a sense of the nano scale, consider that a human hair measures 50,000 nanometers across; a bacterial cell, a few hundred nanometers. The smallest objects visible with the unaided human eye are 10,000 nanometers across.4 Nanoscience is the study of the fundamental principles of molecules and structures with at least one dimension roughly between 1 and 100 nanometers. These structures are appropriately termed nanostructures. Nano-structures are the smallest solid things possible to make and are described as being at the confluence of the smallest of human-made devices and the largest molecules of living things. Nanotechnology is the application of these nanostructures into useful nanoscale devices. Nanoscale is the natural scale of all fundamental life processes, and it is the scale at which diseases need to be met and conquered. Molecular nanotechnology has been defined as the threedimensional positional control of molecular structure to create materials and devices to molecular precision. Nanomedicine is the science designed to employ molecular machine systems to address medical problems. It uses molecular knowledge to maintain and improve human health at the molecular scale, the scale "on which all living cells, and the things that nourish or kill them, operate," according to a report in the New York Times.10 Mechanism of action: Nanotechnology and biology share many similarities. The most complicated organisms are made up of tiny cells that are constructed from nanoscale building blocks: proteins, lipids, nucleic acids, and other complex biological molecules. 2 Nano-technology utilizes tiny nanostructures made from semiconductors, metals, plastic, or glass. Inorganic structures of nanometer scale have already been commercialized as contrast agents. Drug development is a nanoscale activity. Some of the largest and most important categories of drugs are those that work by interacting specifically with DNA or proteins in the body. This class of drug molecules includes aspirin, cisplatin, and other anticancer agents, together with much more complex molecules like beta-blockers, anti-inflammatory agents, antidepressants, and compounds used in AIDS therapy.4 Controlled Drug Delivery The major requirement for implantable drug delivery devices is controlled release of therapeutic agents as a continuous process over an extended period of time. The goal is to achieve a continuous drug release profile consistent with zero-order kinetics where the concentration of the drug remains constant throughout the delivery period.5 Pharmacists are aware that most injectable drugs display first-order kinetics, in that there is an initially high concentration in plasma, followed by an exponential fall in concentration. Toxicity can occur when the peak concentration is above the therapeutic range, while drug efficacy diminishes as the drug concentration falls below this range. Drug delivery systems with a zero-order release rate have several potential therapeutic advantages, including in vivo predictability of release rate on the basis of in vitro data; minimized peak plasma levels and reduced risk of adverse reactions; predictable and extended duration of action; reduced inconvenience of frequent redosing; and improved patient compliance.5 Controlled drug delivery should thus be aimed at improved drug treatment outcomes through rate- and time-programmed and site-specific targeting.6 Nanotechnology now provides the means to achieve this goal. New technologies like molecular modeling, combinatorial chemistry, high throughput screening, and bioinformatics are the engineering tools of the future. According to one researcher, "Future categories of medicinal treatment will comprise the following: mechanism-based small molecules (with several new classes of medicines), therapeutic proteins and other macromolecules, gene regulating medicines and gene therapy."6 Current and Future Developments Developments in nanoscale biomedicine should be able to create implants to release drugs on demand and to monitor blood chemistry. This has been recognized by the National Cancer Institute (NCI). The NCI has committed to a new $144.3 million, five-year initiative to develop and apply nanotechnology to cancer. According to NCI's director, Dr. Andrew von Eschenbach, "Nanotechnology has the potential to radically increase our options for prevention, diagnosis, and treatment of cancer." He also added that NCI's commitment to this cancer initiative comes at a critical time and that nano-technology supports and expands the scientific advances in genomics and proteomics while it builds on our understanding of the molecular underpinning of cancer.7 Among the first nanoscale devices to show promise in fighting cancer and administering drugs are tiny constructions called nanoshells. These devices consist of beads which are about three millionths of an inch wide, with an outer metal wall and an inner silicon core. By varying the size ratio between the wall and core, scientists can tune the shells precisely to absorb or scatter specific wavelengths of light. Gold encased nanoshells can convert these forms of light into heat. There is thus a possibility to fight cancer by selectively binding these shells to malignant cells. Infrared rays would pass harmlessly through soft tissue but generate lethal heat where they strike the nanoshells. In laboratory tests, the investigators have used this selective heating to "cook" tumor cells without harming surrounding healthy ones.2 Nanoshells may also be able to trigger implanted, temperature-sensitive drug delivery devices, releasing a dose only when illuminated with a specific infrared wavelength. One company, Nanosphere Incorporated, is developing molecular testing systems to enable doctors to detect patient predisposition to medical conditions and to allow them to optimize patient drug response based on genetic variations, while simultaneously reducing the occurrence of adverse drug reactions.8 The company has developed a system using gold nanoparticles attached to strands of nucleotides complementary to targets of interest such as the mecA gene, a biomarker associated with clinically challenging methicillin-resistant Staphylococcus aureus. When a target nucleic acid or protein is present, the nanoparticle probes latch onto the match and provide an optical signal indicating that the target has been found. The system is ready to adapt to a full range of targets as soon as clinically relevant markers become available. NanoHorizons, State College, PA, has begun to sell a line of metallic nanoparticles that are compatible with standard polymer manufacturing processes. This means that silver, gold, and other materials that kill bacteria and odor-causing microbes can be incorporated into shoes, athletic equipment, and other plastic or nylon products. The materials can be made into particles shaped like rods or spheres that are designed to greatly increase the available surface area of the metal. Thus far less material is needed to achieve the same results that layers of ordinary bulk metals would achieve. The company claims that its particles are 20 to 100 times more efficacious in killing bacteria than similar metals in bulk form. NanoHorizons has also developed nanoscale materials and devices for drug development research. They would be used with mass spectrometry to screen potential drug combinatorial chemistry products and for general small molecule identification. Biophan Technologies Inc. is another company immersed in nanotechnology. Their strategy is to develop a method of bonding drugs to nanomagnetic materials which respond to externally applied magnetic fields. The drug would be incorporated into a polymer coating and used to treat solid tumors. Magnetic fields would be used to concentrate the drug particles at the tumor site, and modulating the fields would release the drug from the coating to attack cancer cells. Biophan is also using nanotechnology to enhance MRI visualization by developing novel contrast materials to replace gadolinium. These new materials would enhance signal intensity, be less toxic, and be chemically stable. According to the company, nanomagnetic technology will provide materials for controlled drug delivery by directing carriers to a specific location with magnetic fields, which is verified by MRI, and then activated on demand in a limited region. One of the top goals of researchers is to develop new ways to seek out and destroy cancer cells. Nanoshells work by "cooking" cells, but there are other methods. Dr. Ralph Weichselbaum, Chief of Radiation Oncology at the University of Chicago, and Viji Balasubramanian of the Illinois Institute of Technology are collaborating on a project to incorporate a cancer-killer gene into a nanocapsule. The gene elaborates tumor necrosis factor, which is toxic not only to cancer cells but also to healthy cells when injected in large doses. To avoid damage to normal tissue, the nanocapsule is coated with sensors that zero in only on tumor cells. A patient would then be exposed to low-dose radiation or drugs that trigger the gene to make the necrosis factor. 9 A New Curriculum for Pharmacy Schools Burgeoning new discoveries have made the last few years an interesting, exciting, and challenging time for all in pharmacy and related health care. Understanding how drugs work at the molecular level, genetic variations, gene sequences, gene therapy, biomarkers, proteomics, pharmacogenomics, the role of enzyme systems in drug metabolism, and now nanotechnology have added new material to the curriculum at schools of pharmacy and to continuing education programs. Becoming conversant with pharmacodynamics and pharmacokinetics for recently marketed drugs and those on the horizon will require an in-depth knowledge of physics, chemistry, biochemistry, genetics, molecular biology, material science, bioinformatics, and engineering. Additionally, it is arguably most important to consider how to assimilate and disseminate relevant information about these new technology breakthroughs to patients and health care professionals and to do it accurately, clearly, simply, and briefly–not an easy task for today's and future pharmacists. To comment on this article, contact [email protected]. REFERENCES 1. Cancer Facts, National Cancer Institute, http://cis.nci.nih.gov. Feb. 14, 2002. 2. Alivisatos AP. Less is more in medicine. In Understanding Nanotechnology, Warner Books, New York, 2002, pg 56-69. 3. Freitas RA. Nanomedicine Vol. 1: Basic Capabilities–A Review. Landes Bioscience; Georgetown, TX, 1999. 4. Ratner M, Ratner D. Nanotechnology, Prentice Hall, Upper Saddle River, NJ, 2003. 5. Sinha PM, et al. Nanoengineered device for drug delivery application. Nanotechnology 15:S585-589, 2004. 6. Breimer DD. Future challenges for drug delivery. Controlled Release 62:3-6, 1999. 7. NIH News, National Institutes of Health, Monday, September 13, 2004. 8. www.nanosphere-inc.com. 9. Kotulak R. Tiny battlefield in the war on disease. Chicago Tribune, September 14, 2004. 10. Feder BJ. Doctors use nanotechnology to improve health care. New York Times, November 1, 2004. Vol. No: 29:12 Posted: 12/15/04