Drug Delivery
1
Illustrated process of nucleic acid LNP formation. 1) Ionisable lipids (blue) become positively charged at acidic pH and electrostatically interact with negatively- charged nucleic acids (green) to form the particle core. 2) Other lipid species (purple and yellow) assemble around the nascent LNP core as water displaces ethanol and increases the polarity of the environment. 3) Lipids conjugated to polyethylene glycol assemble slowest, forming a protective coating. 4) Cross-section of the fully-formed LNP with nucleic acids encapsulated completely within the particle
2
from this approach are those where current strate- gies are either ineffective – due to poor in vivo sta- bility or bioavailability, for example – or where they cause significant off-target effects, such as anti-cancer agents. Liposome encapsulation of can- cer therapeutics is already gaining some traction as this limits off-target cytotoxicity, and the ‘leaky’ vasculature commonly associated with tumours means that nanoparticles below around 100nm passively aggregate in these sites, where they break down and release their payload.
3 4
Another strategy currently under investigation is the use of liposomes as carriers for subunit vac- cines, in an effort to replace some live attenuated vaccines. For example, the only current tuberculo- sis (TB) vaccine is the BCG, which is very effective in developed countries, but is less effective in regions such as sub-Saharan Africa where there is high incidence of TB. This is because the vaccine is ineffective if patients have already been pre- exposed to the pathogen, and it is not suitable for immunocompromised patients – such as HIV posi- tive individuals – as there is a small risk of the bac- teria being reactivated. In contrast, subunit vac- cines offer improved safety profiles by not expos- ing the patient to whole pathogen, attenuated or otherwise. Designed to present a single antigen – often a single pathogen protein – to the immune system, this avoids many of the issues associated with live attenuated vaccines, but most subunit vaccines suffer from poor efficacy, as they do not generate a strong immune response. By putting these antigen groups on to the surface of lipo- somes, the immune response can be boosted with- out compromising the safety of the vaccine. This approach could also lead to the develop- ment of a generic particle which could be used to accelerate the development and manufacture of new subunit vaccines to counter global health crises. For example, during the recent H1N1 influenza outbreak, by the time a vaccine had been produced, the outbreak was already abating. If you project this on to a more significant pandemic,
20 Drug Discovery World Fall 2017
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