| NANOMEDICINE - Treating and healing on three fronts
Despite the very real progress achieved by medicine, researchers and doctors always seem to come up against the same obstacles: illnesses that are diagnosed too late, medicines that are either ineffective or effective but toxic, and the inability to regenerate the organ or tissue damaged by injury or disease. On these three points – and whether in the face of cancers, accident injuries, cardiovascular, neurodegenerative or immune diseases – the ‘nano approach’ promises crucial breakthroughs.
In vivo viewing
"Conventional contrast agents make it possible to visualise the anatomy, but are not very effective in evaluating the psychological or molecular processes,” explains Andreas Briel of the Schering Social Research Centre in Germany. “That is why nanotechnologies are so interesting as they make it possible to assemble an inert marker that can be identified by the imaging device and a biological ligand that is able to recognise a particular organ or cell type. Because of their small size, these markers penetrate the tissue more easily and improve the image resolution.”
The second field is the generalisation of DNA chips. These in vitro devices make it possible to analyse the gene expression of a cell in just a few hours by means of oligonucleides fixed to a solid support that activate a light or electrical signal when they recognise the complementary DNA sequence. Unknown just a decade ago, these chips are now widely used in diagnosing gene expression disturbances in the cells of very small samples which conventional methods were unable to analyse – in the case of biopsies on patients suffering from stomach cancer, for example.
The ultimate aim of nanomedicine is to identify the tumoural transformation immediately the very first cell is affected. Although there is still a very long way to go, research is beginning to identify the path. Techniques for a rapid analysis of the proteinic combinations of the cell surface – to seek the signature of tumour cells – are at an advanced stage of development. These use protein chips which function on the same principle as DNA chips, but with antibodies that recognise the peptides expressed on the surface of cancerous cells in the place of oligonucleotides.
The race for miniaturisation, in fact, poses some serious technical problems. Jeremy Lakey, Scientific Director of the UK company Orla Protein Technologies, explains: “To make an interface between the biological systems and electronic devices, the latter must be around the same size as the DNA, membranes and proteins, which means we are talking about scales of under 100 nanometres. This implies we must develop nanofabrication methods in the field of electronics.”
The delivery headache
After the diagnosis comes the treatment. Except in special cases (see box entitled ‘Tumour-killing nanoparticles’), the nano approach is unlikely to result in genuinely new treatments. It does, however, hold the promise of a radical improvement on one key point: the delivery of medicines. For a molecule to be effective – whether the result of conventional chemical syntheses or concocted using advanced biotechnologies – it is not enough for it to be able to improve the condition of the sick organ. It must first reach that organ, which is not easy for large molecules such as proteins.
So does that mean the solution lies in using small molecules that can circulate freely in the body? At one point that may have been the view, but “the slow progress in treating diseases such as cancer using molecules with a low molecular weight brought a change of strategy, with the focus now on administering medicines directly into the affected organs”, explains Costas Kiparissides of the Aristotle University in Thessaloniki (Greece). Gene therapy, on which so many hopes were pinned in the 1980s, also comes up against this problem of delivering the DNA medicines to the target cells.
In addition to this scientific question, there are also economic considerations. As Andreas Jordan, Doctor and Director of the MagForce company, admits, “this research into delivery is also a way of giving a second life to molecules that have entered the public domain, by changing their presentation”.
So how can the nano approach revolutionise the delivery of medicines? The answer lies in a very simple geometric fact: for a given mass, the more a substance is contained in small particles, the greater the total surface area with a biological activity able to interact with the receptors on the cell surface.
This explains the attention focused on reducing the size of the systems envisaged for transporting the medicine to its target organ – for example, in tiny bubbles encapsulating the therapeutic molecule made up of single-layer lipids (micelles) or multi-layer lipids (liposomes), or otherwise coated in biodegradable polymers packed with antibodies able to recognise the target cell. All of which brings us to the realms of the very fine engineering of molecular ‘transport’ vehicles that must, at the same time, protect the medicines from breakdown.
As Richard Aljones, of Sheffield University, likes to say, “the most wonderful example of nanotechnology that we know is none other than the living cell, that constructs itself all alone by a process of self-assembly of its parts”. To build these devices, an initial approach therefore is to draw inspiration from the principles at work in living nanometric systems, such as ribosomes or membranous enzymes. Ultimately, it is even envisaged to equip these nanoparticles with remote delivery instructions, so as to trigger the medicine release (by means of electromagnetic waves or infrared stimulation, for example) once the vehicles reach their targets.
The miniaturisation that permits this nano approach also has another advantage in that it makes it possible to envisage innovative ways of administering medicines that are more practical, effective and/or less painful, such as pulmonary administration with nanoparticle sprays or transdermal administration, in particular for unconscious patients.
Cellular differentiation, intelligent materials
Another avenue is also opening up for a command of cellular differentiation, at the heart of stem cell research. “In the traditional approach to cell therapy, the cells are grown in a liquid environment, which limits their differentiation possibilities. We are currently seeking to grow them on a solid surface covered on the nanometric scale with combinations of proteins able to induce their transformation into a desired cell type,” explains Günter Fuhr of the Fraunhofer Institute for Biological Engineering (St Ingbert, DE) and coordinator of the European project CellPROM (Cell Programming by Nanoscaled Devices).
Finally, as we saw in connection with medicine delivery, the nano approach can permit the design of ‘intelligent’ materials able to adapt their behaviour to local biological conditions or external stimulations. “Such materials, when used as both a nutritive and structural matrix, could serve to multiply healthy cells so as to then reimplant them in the diseased organ,” comments Alessandra Pavesio, of the Italian company Fidia Advanced Polymers, who is working on the application of this principle for meniscus regeneration in the European Meniscus project.
Like many industrialists in this sector, Pavesio wants the European regulations to be made more flexible so as to speed up clinical trials on nanomedicine products. David Rickerby, of the European Commission’s Joint Research Centre Institute at Ispra (IT), nevertheless believes that “the present legal framework, which does not differentiate between nanomedicine and conventional products, is sufficiently flexible to integrate innovations of this type at their present stage of development, even if regular evaluation will have to be made to allow for scientific progress”. So it seems that the law will not be caught off guard by the expected scientific and technical changes brought by nanomedicine.