by Brenda E. Barry and JoAnne Shatkin
Nanotechnology is providing exciting new tools and materials to the pharmaceutical industry that have the potential to dramatically improve drug delivery methods. Improving drug delivery is critically important because more than 100,000 deaths per year occur in even those people who take drugs properly (Langer 2006). Nanomaterials (NM) include an array of engineered materials that, by definition, are designed and produced to have at least one dimension that is 100 nanometers (nm) or less (1,000 times smaller than the width of a human hair). Although researchers are currently designing and testing a variety of NM such as carbon nanotubes (CNT), fullerenes, and quantum dots for use as drug delivery devices, their potential toxicity is not currently well understood. This raises an important health question: Can the potential benefits of NM as drug delivery devices be achieved while minimizing the possible risks for patients?
The application of nanotechnology to the life sciences has been termed nanobiotechnology (Mazzola 2005). The very small size and high surface-to-volume ratio of several types of NM makes them ideal candidates for drug delivery (Bianco et al. 2005; Colvin 2003; Hardman 2006; LaVan et al. 2003). Carbon nanotubes (CNT) are simply single sheets of carbon atoms rolled into tubes less than 5nm in diameter. Fullerenes, also called Buckminster fullerenes or buckyballs, are spherical configurations of 60 carbon atoms that resemble a soccer ball (1-2 nm). Quantum dots (QDs) are semiconductor nanocrystals (2- 100nm); bioconjugated QDs are being evaluated as tools for site-specific gene and drug delivery. Some newly generated NM, such as CNT and fullerenes, are completely insoluble in all solvents. However, they can be modified and made more soluble, and potentially less toxic and less immunogenic, by a process called functionalization. Functionalization adds chemical components, such as hydroxyl groups, peptides, or proteins, to NM surfaces.
One or more therapeutic drugs can be attached to or placed inside these NM vehicles. The NM/ drug combinations can also be designed to attach to specific target cells and organs by decorating the NM surface with selected binding agents. This target-specific approach can avoid many of the systemic side effects often caused by drug treatments, such as those from potent chemotherapeutic agents. In addition, the small size of NM/drug combinations can enable them to pass across the selectively impervious bloodbrain barrier for treatment of difficult, and often fatal, brain cancers. Another potential benefit of NM/drug combinations is sustained dosage delivery using time-release drug preparations. In contrast to traditional drug delivery methods, such as injections or pills, sustained dosage delivery can avoid the fluctuations of drug concentrations in the system that may produce adverse reactions and even deaths in patients.
An important question that emerges from the potential use of NM for drug delivery is whether they present new and unanticipated risks for patient health and safety. The same characteristics that provide NM unique advantages also raise concerns about their potential toxicity because common elements like carbon behave differently at the nanoscale level. That is, the properties of graphite do not predict the properties of CNT or fullerenes. One unique property of NM that may contribute to their toxicity is their enhanced reactivity due to the large surface area relative to size. It is also possible that NM will move within the body. Recent research suggests that NM can migrate from one part of the body to another. For example, inhaled NM can pass from the lungs to the blood and on to other organs; and inhaled nanoparticles may reach the brain through the olfactory nerve (Oberdorster 2004). There is also the potential for NM to bioaccumulate, that is, build up in the body. Whether NM can be broken down in the body and eliminated is not known.
The Food and Drug Administration (FDA) is the federal regulatory agency responsible for evaluating the potential health risks of NM/drug combinations. Nanotechnology has been included under FDA’s Critical Path Initiative that is designed to facilitate review of innovative science and technologies (Sadrieh 2006). The FDA has previously reviewed products containing nanoscale materials, such as sunscreens and cosmetics. Whether a new NM submission is categorized as a drug-device, drug biologic or device-biologic product will determine which FDA Center will have jurisdiction regarding regulation. General considerations for NM product approval include characterization, safety issues related to specific delivery route (inhalation, dermal, ingestion, injection), and environmental impact. The FDA recommends monitoring the Federal Register and the FDA Web site for updates on regulatory requirements for NM. The FDA will also hold a nanotechnology public meeting this fall (see related article on page 6).
In conclusion, the potential for nanobiotechnology and innovative NM/drug combinations as medical treatments presents exciting opportunities. Those who work in this emerging field should have up-to-date information about NM toxicology, potential health and safety risks, and the regulatory environment that will impact its transfer to patient use. Understanding both the benefits and the risks of these new NM drug applications can inform good decision-making for drug developers, regulators, and ultimately the consumers and patients who will use this new drug delivery technology.