Scientists believe nanotechnology will revolutionise diagnostics and drug therapies in future. So why are we not seeing more medicinal nanotech products on the market? Susan Birks reports on some of the challenges facing inventors of nano-based therapies
Nanotechnology promises to have a major impact on future medicine. The ability to make materials of a size similar to that of many biological systems is helping the pharma industry to diagnose, target and treat disease in ways not possible before. However, there are huge challenges in getting nanotech concepts onto the market and few have made it as yet.
This disappointing outcome was the driver behind the Nano 4 Life event, held in London earlier this year. Organised by Bio Nano Consulting (a specialist product development consultancy), the Nanotechnology Knowledge Transfer Network (a knowledge-based network for micro and nanotech) and The Wellcome Trust, the event showcased many nanotech projects currently being undertaken. But it also highlighted the challenges the health industry faces in funding, resourcing, manufacturing and marketing such new concepts.
The aim of the event was to bring academics and the health business community together to promote greater understanding of the technologies and to foster greater industry and academic co-operation and thus increase the chance of market success for the nanotech sector.
nanowires and nanotubes
According to Lenard Fass, professor at Imperial College and director of academic relations at GE Healthcare, it is developments in imaging at the nanoscale that are driving many nanotech projects forward. In his review of current nanotech developments he talked of biosensors that could lead to implantable diagnostics - for example, nanowires that measure blood flow or fibrillation, or sensors that can monitor drug delivery. "In future we will have patches that stick on the skin, sensing blood flow," he said.
The therapeutic developments he described included gold nanoparticles that are designed to enter angiogenic blood vessels but not normal blood vessels, allowing tumours to be targeted. He described how collagen encapsulation can envelop the nanoparticles and prevent drug release before the drug gets to its target site, improving drug delivery. And he talked of drug-carrying nanotubes that on reaching their target, can be activated by heat from outside the human body, forcing the drug out of the nanotube to attack the tumour.
Developments in imaging, sensing and drug therapy are being combined to offer new benefits. "In future, we will be able to treat cancer without cutting out tissue," said Fass. "Instead we will have a guidance system, using imaging to show when a therapy has reached its target, stealth pegylated molecules will ensure the drug remains hidden from the immune system, and on reaching the target the treatment can be activated locally, outside the body using either heat or ultrasound."
Despite these advanced concepts, one major hurdle for comapnies is the current lack of knowledge about the physical and chemical effects of such particles. A change in particle size can change a material's physical properties, such as its quantum mechanical effects, optical magnetic properties and electrical conductivity - with good or bad results.
Fass gave several examples: iron oxide, which becomes paramagnetic below about 10nm enabling it to be used as a contrast agent for MRI; nanoparticles that interfere with electron fields in light waves and can thus be used in analytical techniques; and the fluorescence of quantum dots (nanoscale semiconductors) that can change at 2-10nm from blue to red, which is useful in sensing. In addition, particle adhesion properties can change, diffusion times in cells can be faster and nanoparticles can exhibit greater reactivity.
physical changes
It is not only changes in size that count; shape is also important. Certain shapes (e.g. nanorods) can enter cells more easily. These physical characteristics can be beneficial but can also have an effect on toxicity.
Further challenges with respect to nanotech-based therapies were highlighted by Thomas Keller director, biophysical sensors and nanomaterials at GlaxoSmithKline. First and foremost, he said, from a future regulatory point of view, there is a need for greater clarity from regulatory authorities as to what constitutes a nanoparticle: "Is it those in the range 1-100nm or 1nm-1µm?" he asked. Then there is the uncertainty as to the safety of having nanoparticles in the body for any length of time when little is known about the long-term effects.
As a result, the majority of Big Pharma is opting for a low risk strategy of working to re-engineer existing drugs with the aim of increasing bioavailability, said Keller. Even so, "If nanotechnology could reduce a therapeutic dose from four tablets a day, where compliance is likely to be poor, down to one tablet a day, that would have quite an impact on health outcomes".
Even then, industry still faced considerable obstacles in terms of stability and formulation. "We need to ensure the drug isn't taken away by the body's own biological process as soon as it is delivered," he said. "Also there is a lack of understanding of how materials penetrate cell structures. We need more biophysics centres with the skills to carry out fundamental research into biotissues."
proof of principle
Often with new nano-based therapies there may be up to five different types of technology being incorporated into one product. This requires much "proof of principle" work before a technology can be marketed.
Dr Clive Washington of AstraZeneca, believes this requires a fundamental change in the way drug development is set up. Currently only small amounts of NCEs are produced for clinical trials, then once activity has been proven, more material is made available for formulation teams to work on to get the best formulations. With nanotechnology companies will need a lot more of the product at an earlier stage to carry out all the required tests to show it can be sterilised, that it is stable, that it can get it into man and that it works, he said.
"We need to blend discovery and nano-technology together, hand in glove, to make sure both bits work," said Washington. "With nanotechnology, each step is totally different from what has gone before, so there is a steep learning curve." This means products carry a larger financial risk earlier in the development phase and require large amounts of added resource in development.
Even after a concept has been developed, patenting it is becoming increasingly difficult, according Paul Chapman, partner of patent attorneys Marks and Clerk. He said that following the almost exponential growth in nanotech patent filings up to 2003, the number of filings flattened and actually decreased in 2005.
This may be due to patent offices looking more carefully at nanotech patents, he said, or it may be a reflection of difficulties in getting finance. Alternatively, it could reflect the realisation by the industry of the many difficulties in getting such concepts to market.
The added funding required for such new developments is an issue. While universities often produce the blue-sky research, the spin-off companies looking to commercialise concepts then have to find funding to get projects through the expensive feasibility stage.
It is here that The Wellcome Trust can help. According to the Trust's science portfolio advisor Ruth Jamieson, it can offer project grants, personal awards, equipment or biomedical resource grants.
The grants are designed to fund both universities and companies in studies that bridge the gap to get a concept to market. They can range from £100,000 to £8.5m in some exceptional cases - but the average is around £650,000. Of course, the Trust does expect a share of the return.
Nanomechanics speeds discovery of new antibiotics
At the Nano 4 Life event, Dr Rachel McKendry at the London Centre for Nanotechnology described work being carried out in a joint venture between University College London and Imperial College, London, in which nanoscale probes are providing new insight into how antibiotics work and which molecules might provide new antibiotics in the future.
The nanomechanical sensors developed by Dr McKendry's group are sensitive to biomolecular reactions and can be used to discriminate rapidly between drug-sensitive and drug-resistant strains of bacteria, which can increase potential drug candidate screening throughput. The sensors work via molecular cantilevers - different molecular properties cause differential bending of the cantilevers, which can be sensed via differences in fluorescence.
The researchers have used the sensors to study vancomycin, an antibiotic used for several years before any drug resistance was noted. When the researchers looked at why resistance had taken longer to develop with vancomycin compared with other antibiotics, they found it was the molecular shape and type of bonding to the bacteria's cell wall that delayed resistance to vancomycin. However, once the bacteria had mutated, it could reduce the number of bonds to the cell wall and create drug resistance.
By looking at structural analogues to vancomycin the researchers found that oritavancin binds strongly to both vancomycin-sensitive and -resistant peptides. In fact, it binds to resistant peptides approximately 10,000 times more strongly than vancomycin.
Oritavancin has the ability to dimerise and it was discovered that drugs that dimerise bind via both an intermolecular and intramolecular process. The researchers now know that stronger drug dimerisation leads to stronger binding to the cell wall peptides of the bacteria. This also means the drugs can be administered at significantly lower doses.'If we can understand the interaction between antibiotics with the peptides, the bonds that tie them and the entropy, we can begin to work out the types of molecules that will beat the superbugs,' said Dr McKendry.
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Engineering nanoparticles for drug delivery
Ijeoma Uchegbu, Professor of Pharmaceutical Nanoscience and chair of pharmaceutical nanoscience at the school of pharmacy at University College London, is in charge of several nanoparticle projects aimed at improving drug delivery.
Her group has developed a cancer gene medicine using amphiphillic polymers. By changing the number of hydrophobic groups on the polymer they can change the shape of the molecule with interesting therapeutic effect. The amphiphillic polymers can be turned into disc shapes, spheres or tubes and can have a high drug loading (10 times that of an ordinary drug) so therapies do not overwhelm the patient with excipient.
One aim is to improve oral delivery of drugs, and so far the team has found that by using these particles they can improve adsorption of low solubility drugs, such as cyclosporin.
By making drugs more hydrophobic the drug activity is increased as much as 10 times, while by making the drugs more hydrophilic they can improve transport and activity. They currently have a carbohydrate excipient under development with a pharmaceutical company.
The group has also worked with star-shaped dendromers of approx 50nm in size (100 times smaller than the cells in our bodies). The work has led to the production of a water-soluble particle that can be used to target tumours with a tumourcidal gene.
The dendromers created have five different branches and once in the body, one branch latches onto a cancer cell, a second has a chemical trace to image the cancer, the third contains a molecule of folic acid that tricks the cell into thinking of the dendromer as food, and the fourth and fifth branches carry a drug that kills the cancer cell.
Indications so far are that the drug can bring about tumour regression with a single injection, which is superior to drugs being given today. A contract for a feasibility study has already been signed.
Gold nano-particles could treat cancer
A team of researchers at the Technical University of Catalonia (UPC) in Spain have studied the use of gold nanoparticles to detect and treat cancer.
Team leader Romain Quidant, an ICREA researcher at the UPC Institute of Photonic Sciences (ICFO) and a fellow of the Cellex Foundation Barcelona, is working on a strategy called 'plasmonic oncology' that he claims will revolutionise cancer treatment. The idea is to introduce gold nanoparticles into tumour cells, to which laser light would subsequently be applied. The nanoparticles would heat up to such a degree that damaged cells would be completely burnt.
The advantage of nanoparticles over chemotherapy and radiotherapy is that they can be designed to penetrate only damaged cells and so do not damage the healthy ones.
The system has resulted from engineering nanoparticles that can recognise damaged cells and become excellent nanosources of heat. The former is achieved by coating the nanoparticles with molecules that detect and enter cancer cells. The shape of the nanoparticles optimises the generation of heat in response to an external light source. In principle, gold is biocompatible and is readily evacuated by body fluids, but the researchers must make sure that the chemistry involved in the process does not affect the cells.
The interaction between light and gold nanostructures is useful not only for cancer treatments but also for its diagnosis. Quidant is working on a chip that is made up of a multitude of metal nanostructures that are able to send a light signal when they contact with cancer markers.
The chip performs a number of analyses in parallel from a single drop of blood. Each metal nanostructure is coated in receptors that are able to recognise and trap a specific cancer marker. When this happens, the nanostructure responds to the external light differently from when no markers are trapped. Quidant anticipates the detector will be ready within the next 10 years.