Nanomaterials Raise New Challenges

Nanotechnology holds huge potential for improving the design and manufacture of novel medical therapeutics, medical devices, and combination products. Scientists in industry and academia are investigating methods for using minute particles to deliver drugs to specific organs and cells. The methods are prompting the US Food and Drug Administration to encourage public–private collaborations on initiatives to understand the physical and chemical characteristics of nanomaterials and nanoparticles better as part of its Critical Path Initiative. Analysis of new test methods, development of characterization protocols, and agreement on standards promise to help manufacturers move nanoproducts from preclinical testing to commercialization.

Jill Wechsler

Nanotechnology already is being used in a host of consumer and industrial products, including a growing number of drugs and diagnostics. Nanotechnology involves atom-sized particles that are less than 100 millionths of a millimeter in size. By way of illustration, a human hair is about 80,000 nanometers wide. Reducing particles to nanometer size may increase drug product stability and enhance drug absorption and elimination from the body. These features increasingly are touted by makers of cosmetics and sunscreens. Nanoparticles' ability to pass easily through cellular membranes and tissues is raising high hopes for developing cancer therapies that deliver drugs to target tumor cells with less damage to healthy tissues and fewer toxic side effects.

Support for research

The federal government is spending more than $1 billion per year on the White House National Science and Technology Council's National Nanotechnology Initiative. The National Science Foundation is distributing much of that money to fund research projects ranging from semiconductor nanocrystals and nanoelectromechanical sensors to new materials for propellants and explosives and nanoparticles able to remove contaminants from groundwater. The Department of Defense has a large nanotechnology program for military purposes, and the Department of Energy is focusing on new fuels and energy sources that incorporate nanotechnology.

The Department of Health and Human Services has received about $175 million to spend on nanotechnology research. Much of that money has gone to the National Institutes of Health (NIH), which has identified nanomedicine as one of its major initiatives. NIH is allotting $12 million per year to develop a network of Nanomedicine Development Centers to explore how nanotechnology might enhance a basic understanding of biological concepts and cellular processes.

The immediate goal is to characterize the nanoscale components of the cell quantitatively and to examine how to manipulate molecular nanomachines to improve human health. The long-term hope is that this technology will lead to new methods for repairing cellular structures and treating disease by delivering therapies more directly to cells and tissues.

Conquering cancer

National Cancer Institute (NCI) officials are particularly enthusiastic about the great potential of nanotechnology for detecting cancer at very early stages and for developing more effective and less toxic anticancer therapies. Scientists working with NCI's Alliance for Nanotechnology in Cancer are developing nanoscale devices able to identify rare molecular signals associated with malignancy and genome instability. Nanoscale imaging-contrast agents can spot early tumors and metastatic lesions invisible to the eye. Attaching a magnetic resonance imaging (MRI) contrast agent to a nanoscale particle can target the agent to a specific tumor.

Clinical trials for cancer treatments may be able to assess efficacy much earlier by using highly sensitive, nanosized imaging agents and diagnostics able to determine faster whether a therapeutic agent is reaching its intended target and killing malignant cells. The nanotechnological equivalent of a Trojan horse would be able to smuggle chemotherapeutic drugs inside tumor cells. Nanoscale baskets and cages may deliver targeting agents and therapeutic payloads to parts of the body often blocked by biological barriers. Scientists are finding that gold nanoparticles may be extremely effective in delivering treatments or genetic material to cancerous cells as a way to block tumor activity.

And, smart nanotherapeutics could time the release of a drug or deliver multiple drugs sequentially, as well as provide sustained therapy for chronic cancers.

One visible example is "Abraxane," a nanoparticle formulation of "Taxol" (paclitaxel), which was approved by FDA in February 2005 for metastatic breast cancer. By using human albumin to create nanoparticles of the chemotherapy, Abraxis BioScience (Santa Monica, CA, www.abraxisbio.com) was able to produce an injectible suspension without the usual toxic solvent. Because it reduces the severity of side effects, a higher dose of Abraxane can be given to patients, thereby increasing efficacy and minimizing safety problems. The manufacturer is studying additional anticancer indications for the drug and seeks to reformulate other water-insoluble anticancer treatments with albumin nanoparticles.

Similarly, Cell Therapeutics (Seattle, WA, www.cticseattle.com) is developing a nanotherapy for lung cancer ("Xyotax") that binds Taxol to a poly-glutamate polymer to deliver the drug to tumor cells more efficiently. This nanoformulation remains in the tumor longer than other formulations and has fewer toxic side effects.

In addition to cancer agents, biomedical nanoscience is focusing on improving methods for delivering various drugs and biologics to specific cellular targets. This approach may be particularly important in gene-therapy development, which has been stymied by difficulties in finding suitable transport agents to carry nucleic acid to the diseased target cell. New nanoscale structures designed to bind and neutralize anthrax toxins may protect people from this and some infectious diseases.

Researchers at Montana State University (Bozeman, MT, www.montana.edu) are using disarmed viruses and protein-cage technology to deliver therapeutic and imaging agents to specific tissues and cells. The scientists believe that such containers have multiple applications for carrying and delivering antibodies, peptides, and other therapies and have licensed this technology to SpeciGen (Palo Alto, CA, www.specigen.com) to develop protein-cage drug delivery products.

Regulatory concerns

In response to these developments, FDA is expanding its expertise to assess such products better as they move from laboratories to commercial development. One issue is the need for added scrutiny of safety concerns related to nanotherapies, starting with the numerous sunscreen products incorporating nanoformulations that are clear and more readily absorbed. The Center for Technology Assessment (CTA) considers these products dangerous and filed a petition with FDA in May calling for the agency to pull all over-the-counter nanotechnololgy-based sunscreens off the market until manufacturers can prove they are safe and present no hazard to public health.

The petitioners want FDA to revise its 1999 sunscreen monograph to require additional analysis of nanoparticles of zinc oxide and titanium dioxide now used in some of these products and to require labeling of all nanoparticle ingredients. This coalition of environmental and health organizations also calls for new regulations for drugs containing nanoparticles, starting with an advisory opinion from the FDA commissioner clarifying that engineered nanoparticles are fundamentally different from bulk substances (see sidebar, "Sunscreens raise alarms").

Sunscreens raise alarms

FDA weighs concerns

Many of the issues raised in the CTA petition have been under scrutiny at FDA for many years. Nanoparticles have been used in the research and development process for drugs and biologics to enhance biological markers, probe DNA structures, purify biological molecules, enhance MRI agents, and develop drug delivery mechanisms, explains Nakissa Sadrieh, associate director for research policy in the Office of Pharmaceutical Science of the Center for Drug Evaluation and Research (CDER).

FDA has not detected any safety concerns related to particle size in drug products, however, and believes that the existing battery of preclinical safety tests, which require the administration of several high doses to multiple animal species for a long period of time, would uncover relevant safety problems. FDA has regarded nanomaterials as substantially the same as larger counterparts, Sadrieh points out, and has not required special testing of nanomaterials.

At the same time, FDA recognizes that nanoparticles in drugs and cosmetics may gain access to tissues and cells more easily and that little information is available about how long nanoparticles remain in the body, how they are eliminated from tissues and blood, and whether they have additional effects on cellular functions or on different cell types. FDA would like more research about whether the inhalation of nanoparticles raises specific safety issues, whether local sensitization arises from subcutaneous injection of nanoproducts, and whether dermal applications could spread to local lymph nodes. The agency advises manufacturers to assess any differences in the absorption, distribution, metabolism, and excretion profile of nanoparticles compared with larger particles of the same drug, including whether they have accurate methods for measuring drug levels in the blood and their eventual elimination from the body.

Manufacturing challenges

Efforts to ensure the safety of nanomaterials also require manufacturers to assess fully how nano-sizing drugs affects their dissolution rate, solubility, and onset of therapeutic action. Although these features may permit lower dosages and simplify administration, they also can raise concerns about safety and product quality.

A prime challenge for manufacturers is to ensure reproducibility and quality of nanotechnology products. Critical quality attributes include:

• particle size and size distribution;

• surface area, surface chemistry, porosity;

• hydrophilicity, surface-change density;

• purity and sterility;

• stability (aggregation, protein interactions).

Characterization of nanotechnology products may raise unique considerations (see sidebar, "Issues to consider during nanotechnology product characterization"). Manufacturers must identify available tools for assessing the critical physical and chemical properties of the products, including residual solvents, processing variables, impurities, and excipients. Validated assays are important for detecting and quantifying nanoparticles in tissues and medical products and for determining how physical characteristics may affect product quality and performance.

Issues to consider during nanotechnology product characterization

All of these issues are important in demonstrating full control of a production process and justifying drug-release parameters and bioequivalence-testing approaches, Sadrieh points out. The process of developing test methods and specifications that clearly can control product and process to scale up to mass production may be complicated by a lack of reference materials and standards. Additional standard test methods may be needed to develop nanoparticles for drugs and biologics.

To assist manufacturers in developing appropriate safety and quality-control methods and to ensure appropriate regulatory strategies, FDA is conducting laboratory research to understand better the ability of preclinical screening tests to identify potential risks and toxicities. CDER scientists are examining the effect of particle size on sunscreens that contain zinc oxide and titanium dioxide nanoparticles, as well as issues related to the manufacture of nanoformulations and the characterization of physical and chemical properties. Tests are being conducted to determine whether excipients or different process and formulation variables may affect nanotechnology product characteristics, overall stability, and bioavailability. The Center for Biologics Evaluation and Research is developing a nanoparticle-based assay for detecting blood-borne viruses and for testing blood-cell compatibility of nanomaterials. Additional FDA research is evaluating skin penetration (in humans and animals) of nanoparticles in sunscreens.

The future of nanotechnology

At FDA's Science Forum in April, a panel of scientists discussed various nanotechnology developments affecting drugs and medical products. The researchers addressed factors related to toxicity and preclinical characterization of nanomaterials as part of an overview of emerging applications of nanotechnology for biology, imaging, and medicine.

FDA expects that nanotechnology will yield more combination products with multiple components, including a delivery system, therapy, imaging agent, and targeting agent. Such complex products will create challenges for FDA's Office of Combination Products in determining the primary mode of action, which is the basis for assigning products to a lead Center for application review.

In addition to the cancer agent Abraxane, FDA has approved nanoscale liposomes and microemulsions as well as MRI imaging agents and targeting agents. One antibacterial wound dressing incorporates silver nanoparticles, and a nano-based dental restorative has been created. FDA anticipates more nano-based new drugs and imaging agents will be on the way soon. Its Office of Science and Health Coordination oversees nanotechnology activities throughout the agency, including its participation on government-wide nanotechnology committees. CDER also has established a Nanotechnology Working Group to develop position papers and identify regulatory concerns in this area.

These issues are slated to be discussed in October at an FDA public meeting about scientific and regulatory issues related to products containing nanotechnological materials. The meeting will fit FDA's Critical Path Initiative, which aims to identify scientific hurdles that may inhibit the use of nanotechnology in medical product development. FDA hopes attendees will report on new nanotech drugs, on what scientific issues FDA should address, and on other regulatory concerns.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com