Delivering drugs by applying the active ingredient to the skin, dermal delivery, offers many potential benefits in pharmaceutical, dermatological, and cosmetic applications, and yet the interactions and transport mechanisms across the skin barrier are not yet thoroughly understood at the molecular level. Nanogels have attracted particular interest as possible carriers, because of their high surface-to-volume ratio and ability to form stable colloidal systems. Their chemical structure can be tailored to achieve particular physicochemical properties, and to respond to stimuli, such as temperature, by undergoing rapid conformational changes and altering their volume. In work recently published in the Journal of Colloid and Interface Science, a team of researchers from Queen Mary University of London used neutron reflectivity to study the interactions between thermo-responsive N-isopropylacrylamide based nanogels, cross-linked with 10%, 20% and 30% N,N'- methylenebisacrylamide, and skin lipid multi-bilayers models. They also investigated the effect of the penetration enhancer benzyl alcohol on the interactions between nanogels and lipid multi-bilayers.
Nanogels as dermal delivery systems
In order to design highly-efficient and tailored dermal drug delivery systems, researchers need a more thorough understanding of the relationship between chemical structure and interfacial behaviour and its impact on skin permeation. Thermo-responsive N-isopropylacrylamide (pNIPAM)-based nanogels have attracted considerable interest because of their potential to be used as dermal drug delivery vehicles, and researchers from Queen Mary University of London studied the interactions between NIPAM nanogels cross-linked with MBA (in molar ratios of 10, 20 and 30%) and pure ceramide lipid multi-bilayers and ceramide/cholesterol/behenic acid mixed lipid multi-bilayers. They also investigated the effect of benzyl alcohol (a penetration enhancer that promotes the transport of active reagents across the skin barrier) on the interactions between nanogels and lipid multi-bilayers.
The study was carried out using neutron reflectivity on the SURF and INTER instruments. The team investigated the interactions of nanogels with both ceramide and mixed ceramide/cholesterol/behenic acid (molar ratio 1:0.3:1) lipid multi-bilayers in contact with water, supported on a single crystal Si substrate by means of contrast variation (isotopic substitution). Mixed models were used to represent a more idealised skin composition.
As Dr Ali Zarbakhsh explains, “Neutron reflectivity is a powerful technique for in situ characterisation of supported lipid membrane systems at interfaces, offering a resolution of less than a nanometer, being non-destructive and capable of applying contrast variation which can be used for highlighting specific parts of the system." Prof. Marina Resmini also adds that 'the study of the behavior of nanogels at the interfaces using neutron reflectivity is very innovative and allows us to learn important properties of these materials'.
Neutron reflectivity findings
The results showed that the ability of nanogels to associate with skin lipids to form water-dispersible complexes increased with the percentage of cross-linker (MBA). This interaction increased with temperature in the case of ceramide lipid multi-bilayers. As the hydrophobicity of nanogels increases with cross-linker content and temperature, the researchers concluded that the nanogels mainly associated with skin lipid molecules through hydrophobic interactions. The presences of benzyl alcohol, a well-known skin penetration enhancer, caused an enhanced depletion of lipids.
Membrane fatty acids play a role in facilitating membrane transport, and the results of these experiments suggest that not all fatty acids remain in the membrane. The complex formation of nanogels and free fatty acids increases the surface activity of nanogels and results in depletion of some lipids facilitating the penetration of the nanogels into the system. The focus of further work using additional contrasts will be to confirm this and understand fully the role of membrane fatty acid in facilitating transmembrane transport.
It's also possible that the observed enhancement effect is a result of weakened neighbouring molecule interactions and the changes in the conformation of lipid bilayers, upon intercalation of benzyl alcohol into the bilayers and also hydrophobic complex formation with nanogels.
This work provides important advances in understanding the mechanism by which NIPAM-based nanogels are able to interact with multi-bilayers, which can ultimately contribute to the development of novel nanoparticles able to interact and penetrate biological barriers.
Sun H et al. Interactions of NIPAM nanogels with model lipid multi-bilayers: A neutron reflectivity study. Journal of Colloid and Interface Science 536,598-608 (2019). DOI:10.1016/j.jcis.2018.10.086.