Passive targeting, however, appears to be closer to the mark. Indeed, even the size of the vector or changes on its surface can be used to reach the target. For example, we know that round an inflamed or tumoral site, the internal lining of the blood vessels (endothelium) changes, presenting fenestrations which are approximately 500 nanometres in diameter. If nanovectors have a smaller diameter (between 100 and 200mm), they can slide into the fenestrations and specifically cluster around these points. Passive targeting simply uses the size of the vector, without specifically and immunologically recognising the target or using a particular target receptor.

Disguising progress

As mentioned above, active ingredients are often biological molecules, which risk being identified by opsonines in the immune system as soon as they enter into the bloodstream, and will thus be destroyed before they reach their target. The most widely used tactic is therefore to 'disguise' them so they can move about unseen.

The first generation vectors were simple liposomes: the active ingredient was encapsulated in a lipid bilayer. But these first generation nanovectors were generally recognised by opsonines as soon as they were injected, and ended up in the liver, where they accumulated. They are useful, therefore, for treating ... the liver. Indeed, they have been used to target hepatic cancers.

To avoid opsonisation, some scientists had the idea of grafting polymer molecules onto the liposomes (polyethlylene-glycol = PEG), which made the liposomes 'hairy', thus disguising their immunological patterns which could be identified by the opsonines. These vectors are today known under the name of PEGylated liposomes. For the record, they are also known as 'stealth liposomes' because they were developed during the Gulf War, when the general public first heard mention of stealth aircraft, hence the nickname. The hairy liposomes were said to have 'prolonged vascular persistence' because they could remain for long periods behind their 'masks' in the general circulatory system, which gave them time to infiltrate the points where the vascular endothelium was festrated, i.e. often around the diseased organ.

'But we realised that protecting the active molecule and transporting it to the place were it has to act was still not enough', continues Piel. 'We thus moved towards complexifying these vectors, with a third generation of liposomes (adding biomolecular recognition markers, such as folic acid, antigens, peptides, etc., which would enable more precise targeting - thus overlapping with active targeting projects) and probably a fourth generation. This fourth generation, as well as involving a complex envelope and active molecule, include molecules which react to a stimulus to release the active ingredient.' This is yet another additional, and unexpected, challenge.