Releasing at the right time

Imagine that the nanovector has arrived intact at the right place: its mission isn't yet over. If the active ingredient which it encapsulates has not been released en route, it now has to be released at the target cell. To do so, the first step is to ensure that it can penetrate the cell, which is most often done through endocytosis, and apparently without too many difficulties.

But then, how is the active ingredient released? Different tricks are used to attempt to make the capsule react to stimuli which it will only encounter at the intracellullar level. 'For example,' explains Piel, 'as we know that the pH is more acidic at the intracellular level, and in particular in tumoral cells, we may choose components which change structure when the pH becomes more acidic to encapsulate the active ingredient, meaning that the vesicle bursts. '

External stimuli can also be used, for example by choosing lipids which are sensitive to temperature. These can be injected systemically into the veins, then placing a heat source near the tumour (although the temperature of the tumour is generally slightly higher than that of neighbouring tissues). 'There is already a real example of this approach', says Piel. 'It is a second generation liposome which is sensitive to heat, using doxorubicin (a chemotherapy agent which has significant cardiac toxicity), which will appear on the market in 2013.' Administration of this product, targeting liver and lung cancer, will be combined with specific techniques to heat the cancerous sites.

It is also possible to activate the active ingredient using light or magnetic stimuli. For example, there is a drug which can be used against retinal macular degeneration, which reacts to illumination of the retina by releasing the active ingredient. Some researchers also dream about incorporating tiny magnetic particles which would react to variations in the magnetic field, or visualising agents (metallic particles) so that medical imaging could check that the active ingredient has arrived at its destination. 'We are encountering many more barriers than we thought at the beginning, which explains why there are not yet many products on the market', summarises Piel. 'We'll need to work together on various levels to be able to effectively deliver active ingredients.' This will also increase their cost ...

Currently, there are only around fifteen specialities which are being marketed in the world, of which 13 are liposome-based. These vectors can only be used in hospital environments.

Truly multidisciplinary

In practical terms, how is a vector produced? 'Chemists create 'tailor-made' polymers', explains Piel. Thus, polymerists from the University of Mons develop for us, new polymers designed to react to a whole series of stimuli. For example, to interact with si-RNAs, which have negative charges, we need polymers which carry positive charges. We therefore combine them with lipids or cationic polymers. The goal is also to find the right relationship to eventually end up with an object which has a slightly positive charge - but not too much, otherwise it is toxic! - because the cell surface contains negative groupings. We therefore need to play on the affinities between the particle and the cell.' In short, a particle has to be produced with the right size, the right charge, and with sufficiently efficient polymers to disguise the active ingredient from the 'eyes' of the opsonines ...