Matthew Brace investigates current and future technological developments in nanomedicine
In the rapidly expanding world of nanotechnology, the pharmaceutical and healthcare sectors are of the utmost importance. Vast amounts of money are being pumped into nanotechnology research, with Euro 90m being earmarked for nanomedicine under the European Union's (EU) outgoing sixth framework programme for research alone: more money is expected to be spent under the seventh framework programme, which should start in January 2007.
Nanomedicine uses engineered devices and nanostructures with active components or objects measuring from one nanometre (one billionth of a metre) to hundreds of nanometres. They may be included in a micro-device or a biological environment. The focus, however, is always on nanointeractions within a framework of a larger device or biologically, within a sub-cellular (or cellular) system.
The scope of applications includes analytical tools, nanoimaging, nanomaterials and nanodevices, novel therapeutics and drug delivery systems, as well as clinical, regulatory and toxicological issues.
A December 2005 report produced by the European Medical Research Councils (EMRC) and the European Science Foundation (ESF), entitled "Scientific Forward Look on Nanomedicine", argued that "to realise nanomedicine's full potential, important challenges must be addressed. New regulatory authority guidelines must be developed quickly to ensure safe and reliable transfer of new advances in nanomedicine from laboratory to bedside".
Two priority areas are drugs and drug delivery systems, encompassing nanoscale assemblies, which can be relatively simple. Examples of these areas are nanoemulsions, nanoparticles or polymer conjugates (of proteins or drugs), or complex multicomponent systems, containing drugs, proteins or genes, as well as an array of targeting ligands and signal systems to enable in vitro or in vivo detection.
Drug discovery builds on identification of new molecular targets which are being used to design "perfect fit" drug molecules with more specific therapeutic activity. These efforts continue via the screening of natural product molecules to identify candidates with pharmacological activity, and the preparation of carefully tailored synthetic low molecular weight drugs via traditional medicinal or combinatorial chemistry. Nanofluidics is being used for targeted synthesis, and nanodetection is used for target identification. Also important is the discovery of natural macromolecules (including antibodies, proteins and genes) that have inherent biological activity.
Drug delivery is being approached by developing new multifunctional, spatially ordered, architecturally varied systems. The ESF would like to see systems in place "to enable the rapid realisation of clinical benefit (within five years)".
In Melbourne, Australia, the company Nanovic said a market analysis performed in March 2004 suggested that "nanotechnology is currently applied in up to 1% of drug delivery technologies under development; by 2015, as much as 14% of drug delivery technologies may use nanotechnology".
innovations
The drug delivery systems entering the market have been designed to achieve disease-specific targeting, to control the release of the drug so that a therapeutic concentration is maintained over a prolonged period of time, or to provide more convenient routes of administration (eg, oral, transdermal, and pulmonary) and reach locations in the body that are traditionally difficult to access, such as the brain. Via the use of coatings, ever more sophisticated devices are emerging that allow localised controlled release of biologically active agents.
Advances make use of naturally occurring carbon nanotubes. Biophan Technologies, US-based developer of next-generation medical technology, announced in March 2006 that it had filed a patent on novel drug delivery technologies involving applications of nanotubes found in halloysite clay, as part of its collaboration with New York-based company NaturalNano.
Biophan and NaturalNano are collaborating to develop products using the nanotubes as advanced drug delivery systems in a number of proprietary biomedical applications. Biophan's newly filed patent application covers biomedical uses of the nanotubes for a range of products, including bandages and wound healing applications.
Also in March 2006, University of Illinois scientists announced that they had discovered that nanoparticle-studded capsules could be used to "armour" lipid molecules, making them very durable. That would make the capsules useful for delivering drugs to specific sites in the body or delivering DNA, proteins and other genetic material in gene therapies. The nanoparticle-covered capsules are made of biocompatible lipid molecules that could be covered with other reactive molecules to become molecular-scale sensors to detect toxins, tumours or similar properties.
Drug delivery could one day become ultra-precise, thanks to the creation in August 2005 of the 'smart bio-nanotube' by researchers at the University of California, Santa Barbara. They combined one natural component of a cell with the synthetic analogue of another component to create the nanoscale hybrid. The nanotubes are 'smart' because they can open or close at the ends, depending on how the researchers manipulate the electric charge on the two components. In theory, a nanotube could encapsulate a drug or a gene, and then open on command to deliver the contents where it would have the best effect.
Another key drug delivery advance was made in 2005 at the University of California, Los Angeles, by researchers studying naturally-occurring nanocapsules known as vaults. The team discovered that a vault is a nanoscale 'Trojan Horse', smuggling foreign molecules past cellular membranes that are designed to keep them out.
Once the foreign molecule was secreted within the vault cavity, the researchers fed the vault into the cells and they accepted them. They proved both the vaults and their smuggled cargo could survive by previously adding green dye protein and watching it glow from inside the cell membrane.
The possible applications of such an advance include:
- Therapeutic delivery such as targeting cancer drugs directly to a tumour cell without harming healthy tissue;
- Enzyme delivery to replace missing or defective enzymes;
- DNA delivery to correct genetic mutations;
- Timed release of drugs, enzymes and DNA;
- Protein stabilisation to increase their life spans;
- Biological sensing;
- Detoxification by extracting and imprisoning toxic metals or other cellular poisons.
The University of Illinois has produced tiny, implantable carbon nanotube sensors that might one day allow diabetics to continuously monitor glucose levels without drawing a drop of blood.
The sensor is a tiny, needle-like tube full of the modified nanotubes, designed to be implanted just under the skin. To read the glucose level, a watch equipped with a laser pointer illuminates a patch of skin over the sensor while an infrared light detector monitors the response at the same time.
In another development, carbon nanotubes" capability to fluoresce naturally is being used. The tubes glow at one wavelength of light when illuminated by another wavelength. The wavelengths emitted from the nanotubes are in the near infrared region and are slightly shorter than the infrared waves produced by the human body.
Near infrared light can pass through human tissue but is invisible, so even though we cannot see an implanted and glowing carbon nanotube, its brightness could be measured with devices that see near infrared light.
From this a class of sensors could be produced to operate within the human body and transmit optical signals outside it to give information about local biochemical concentrations.
Another future focus is to build nanostructured scaffolds for tissue engineering, stimuli-sensitive devices for drug delivery and tissue engineering, and physically targeted treatments for local administration of therapeutics (via the lung, eye or skin, for example).
The ESF 2005 report said cancer, neurodegenerative and cardiovascular diseases have been identified as the first priorities. Longer term priorities include the design of synthetic, bioresponsive systems for intracellular delivery of macromolecular therapeutics (synthetic vectors for gene therapy), and bioresponsive or self-regulated delivery systems including smart nanostructures such as biosensors that are coupled to the therapeutic delivery systems.
The ESF's 2005 report said: "It is clear that the contribution of nanotechnology will continue to grow in the future, and it is widely believed that effective delivery gene therapy and other macromolecular therapeutics will be realised only with the aid of multicomponent, nanosized delivery vectors."
The report also called for new materials to be developed "for sensing multiple, complicated analytes in vitro, for applications in tissue engineering, regenerative medicine and 3D display of multiple biomolecular signals".
"Telemetrically controlled, functional, mobile in vivo sensors and devices are required, including construction of multifunctional, spatially ordered, architecturally varied systems for diagnosis and combined drug delivery (theranostics). The advancement of bioanalytical methods for single-molecule analysis was seen as a priority," the report said.
combating cancer
In March 2006, researchers at the Georgia Institute of Technology announced they had found a safer and more effective way to detect and kill cancer cells. By changing the shapes of gold nanospheres into cylindrical gold nanorods, they can detect malignant tumours hidden deep under the skin, like breast cancer, and selectively destroy them with lasers only half as powerful as before - without harming healthy cells.
A Georgia Tech report said that last year a father-and-son research team, Mostafa El-Sayed (director of the Laser Dyanamics Laboratory) and Ivan El-Sayed, showed that gold nanoparticles coated with a cancer antibody were very effective at binding to tumour cells.
When bound to the gold, the cancer cells scatter light, making it very easy to identify the noncancerous cells from the malignant ones. The nanoparticles also absorb the laser light more easily, so that the coated malignant cells only require half the laser energy to be killed compared with benign cells. This makes it relatively easy to ensure that only the malignant cells are being destroyed.
Now, the team has discovered that by changing the spheres into rods, they can lower the frequency to which the nanoparticles respond from the visible light spectrum used by the nanospheres to the near-infrared spectrum. Since these lasers can penetrate deeper under the skin than lasers in the visible spectrum, they can reach previously inaccessible tumours.
'For laser phototherapy treatment of skin cancer or, for diagnostic biopsies, the spheres are fine, but for phototherapy of cancer deep under the skin, like breast cancer, then one really needs to use the nanorods treatment,' says Professor El-Sayed.
Sticking with the various benefits of nanospheres and nanorods, US researchers have created nanorice, which combines the best properties of the two most optically useful nanoparticle shapes. Appropriately, the team was from Rice University in Texas.
As nanorice can be used to focus light on small regions of space, the scientists plan to attach grains to scanning probe microscopes.
Such nanoscale structures act as super-lenses that can amplify light waves and focus them to spot sizes far smaller than a wavelength of light. By moving the grains next to proteins and unmapped features on the surfaces of cells, they should get a far clearer picture.
It is hoped that nanorice will have the field intensities needed to characterise biomolecules such as proteins and DNA that adsorb on the particle.
Overall, there will probably not be a large mass market for nanomedicine for some years but the on-going commitment of small and large companies is a vital sign of confidence.