It's a small world

In the popular view of nanomedicine, miniature robots equipped with a set of tools will one day patrol the inside of the body, cleaning up atheroslerotic plaque, zapping cancer cells, and generally performing repair and maintenance. This highly futuristic scenario owes much to a vision presented by Eric Drexler, the pioneer of nanotechnology, in the 1980s. In reality, nanomedicine is making a slow, but steady, impact on the pharmaceutical industry. In 2006, Nature Materials estimated that there were approximately 130 nanodrugs or delivery systems in development across the globe,¹ which, although is not many compared with the number of small molecules and biologics in the pipeline, is enough to create an intriguing new product category.

Susan Aldridge

The nanoscale

Nanotechnology involves engineering functional systems at the molecular scale. While Drexler is credited with the major development of the field, the concept can be traced back to the physicist Richard Feynman who, in 1959, said: "There is plenty of room at the bottom" when referring to the possibilities in the nanoworld.² The nanoscale is really the molecular scale, with small organic molecules lying at the lower limit of this range, viruses towards the upper end, and protein molecules and other biologics somewhere in the middle. Nanotechnology is well established today in the computing, energy and electronics sectors, but less so in pharma and biotech.

Nanomedicine is, put simply, the application of nanotechnology to medicine. In its first issue, the journal Nanomedicine adopted a more precise definition of nanomedicine as 'the use of materials, of which at least one of their dimensions that affects their function is in the scale range 1–100 nm, for a specific diagnostic or therapeutic purpose.'³ Then there is bionanotechnology — a broad and sometimes vague term that refers to the biomedical or biological application of nanotechnology. This can encompass the use of biomolecules themselves as nanodevices. Nanobiotechnology is another term in common use, which although is hard to define precisely, is generally understood as the use of nanotechnology in biotech applications.

For the pharma and biotech industries, the advantages of nanomedicine lie mainly in its ability to make drugs with better pharmacokinetics and bioavailability. "Materials can have very different properties at the nanoscale," explains Dr David Sarphie, CEO of Bio Nano Consulting, a joint venture between Imperial College and University College (all UK) that advises on the development and commercialization of new biomedical products in the nanotechnology area. For example, carbon nanotubes, which are an allotrope of carbon made of long cylindrical tubes, are exceptionally strong compared with more conventional forms of carbon.

Nano innovation

The nanomedicine products already on the market fall into five categories: nanoparticles, nanocrystals, dendrimers, liposomes and micelles. The Fraunhofer Institute for Manufacturing Technology and Material Research Applications (Germany) and Bio-Gate, Nürnberg, a spinout of the University of Erlangen (Germany), have revived silver, a traditional antimicrobial, in the form of nanoparticles. Their technology can be used to coat medical instruments and devices, wound dressings, lab coats and bandages to protect patients against infection. With antibiotic resistance reaching epidemic proportions, new approaches to fighting infection will be welcomed. In a related development, smelly feet can be overcome by wearing socks impregnated with silver nanoparticles that kill the bacteria responsible for foot odour.

Elan (Ireland) has commercialized its NanoCrystal technology, which involves reducing the size of crystalline drug particles into the nanoscale to increase the drug surface area and aid the dissolution of poorly water-soluble compounds, thereby improving bioavailability. The first nanocrystal product is a new version of the immunosuppressant sirolimus. As it is a solid dose formulation, it is more easily stored and administered than the previous oral solution that needed to be refrigerated. As patients are usually on sirolimus for life, the advantages are clear. Elan has also offered to help other companies put their products into nanocrystal form.

Another emerging class of nanodrug is the dendrimer, a precisely defined synthetic complex molecule. A dendrimer is synthesized around a core molecule with branching functional groups, to which other branching molecules can be added in layers to create a molecule with many functional groups on its surface. The nature of these groups can be tightly controlled and the advantage of a dendrimer is that it can activate many receptors simultaneously, whereas a small molecule will only interact with one receptor. Starpharma (Australia) is developing dendrimers based on the amino acid lysine (with its two branching amino groups) for a variety of applications including HIV, genital herpes, drug delivery and small interfering RNA delivery, and already has a vaginal microbiocide dendrimer product on the market for HIV, bacterial vaginosis, HPV and contraception.

The author says...

Liposomal and micellar formulations of drugs bring them into the nanoscale, and have been used in a number of controlled-release systems including: Doxil (Alza, USA), a liposomal formulation of the anticancer drug doxorubicin; Medicelle (NanoCarrier, Japan), a micelle-based technology for anticancer drugs; and Basulin (Flamel Technologies, France), a long-acting insulin. Meanwhile, conjugation of drugs with polyethylene glycol (PEG) is another popular nanotech application that improves the half-life of drugs, such erthyropoetin for anaemia, and interferon-alpha for hepatitis C, meaning that the patient has to take fewer doses, which can improve the quality of life for the patient in terms of fewer injections.

The unknown

Manufacturing nanomedicines is conducted either by breaking down a material (nanocrystals) or building one up (dendrimers); for example, Elan makes its nanocrystals by milling the drug substance using a wet-milling technique. The particles are prevented from sticking together by surface absorption of stabilizers, resulting in an aqueous dispersion that behaves like a solution and can be further processed into finished dosage forms. Purification is not as straightforward as for a small molecule and there will always be a size distribution in a PEGylated product as polymer molecules vary in length.

Whether improved purification methods will provide clinical benefits remains to be seen. "Pharma has not jumped headfirst into nanomedicine," says Sarphie. There are potential risks with particles at the nanoscale as it is still relatively unknown territory. A recent paper in Nature Nanotechnology by Ken Donaldson and his team at Edinburgh's Safety of Nanomaterials Interdisciplinary Research Centre (UK) highlighted the potential hazards of the carbon nanotube.⁴ Donaldson points out that there are many resemblances between carbon nanotubes and asbestos fibres: they are both very thin (10–200 nm), are either long and straight or may tangle, and are very tough, durable and not readily soluble in tissue. The team examined cells lining the pleural cavity that are the target of mesothelioma in an animal model, a cancer caused by asbestos fibres, and found that long carbon nanotubes caused damage, inflammation and scarring of the mesothelium, similar to that found with asbestos. However, the short carbon nanotubes caused no damage. The work raises several queries regarding the safety of carbon nanotubes, but the question is would medicines based on carbon nanotubes have the same adverse impact on the mesothelium as asbestos? It has already been proposed that the nanotubes would be good for delivering short interfering RNA into cells to regulate gene activity, but the answers regarding safety are needed fast as the last thing the emerging field of nanomedicine needs is a catastrophe.

Meanwhile, another report suggests that silver socks may have an adverse effect on the environment.⁵ In experiments where socks impregnated with silver nanoparticles were washed, the particles leached into wastewater. Entering the water supply in this way could upset microbial ecosystems by killing off certain species of 'friendly' bacteria.

Despite the concerns, there is still plenty of room for innovation in nanomedicine beyond drug delivery applications and for investment, and some of the benefits may come from new drug discovery and development tools rather than nanodrugs themselves.

References

1. Editorial, Nanomedicine: A matter of rhetoric?, Nature materials, 5, 243 (2006).

2. R.P. Feynman, There is plenty of room at the bottom (1960). www.zyvex.com/nanotech/feynman.html

3. K. Kostaleros, Nanomedicine, 1, 1–3 (2006).

4. K. Donaldson, Commentary on Nature Nanotechnology Paper (2008). www.safenano.org/Uploads/Donaldson_NatureNanoCommentary.pdf

5. P. McKenna, Smelly sock treatment leaks silver nanoparticles (2008). http://technology.newscientist.com/channel/tech/nanotechnology/dn13602-smelly-sock-treatment-leaks-silver-nanoparticles.html