But it’s not just nicotine replacement therapy that utilises such medicated patches; transdermal delivery systems in the form of creams, gels and patches make an important contribution to a number of medical treatments. However these systems are yet to achieve their full potential as an alternative to both oral delivery and hypodermic injections. In order for novel nanoparticles to make a full impact on pharmaceutical and personal care formulation, a greater understanding of their mechanism of transport across the skin barrier at a molecular level is needed. Scientists from Queen Mary University of London have been developing thermally activated nanogel delivery systems and are using neutrons to look at the interaction between these drug carriers and the skin.​

Could thermo responsive nanogels be hot on the trail of other drug delivery systems?

Transdermal drug delivery offers many potential benefits in pharmaceutical, dermatological, and cosmetic applications, however the challenge is for the active ingredients to be able to cross the outer-most barrier of the skin, the stratum corneum. This barrier, is very strong and designed by Nature to protect the body, by keeping essential nutrients in and pesky pathogens out. Most drugs, as a result of their structure and properties, are not able to cross the skin barrier and therefore require a delivery system.

Nanogels are three-dimensional cross-linked polymeric networks characterised by a high surface to volume ratio. Some nanogels can be synthesised using special components, so they are responsive to external stimuli such as temperature or  pH, and they can alter their structure with response to these environmental factors, helping drugs to cross the skin more efficiently. But how do they work? And how can they be optimised? A group of scientists led by Dr Ali Zarbakhsh and Professor Marina Resmini, Queen Mary University of London, have been using neutrons to find out.

“We are looking at developing novel nanogels to be used for transdermal drug delivery”, explains Ali. “Our research is focused on resolving structures at interfaces in order to answer some key scientific challenges such as: how do our nanogels overcome biological barriers? How do they affect the conformation of the membrane, how do they transport through the epidermal layers and how could this be optimised?”

“Transdermal drug delivery systems offer a great potential for convenient and pain-free drug administration for patients with the added advantage of evading the first pass metabolism. They are generally inexpensive too, in comparison to other therapies. However biological membranes in the skin are a barrier to these agents and in order to design the future generation of highly efficient and biocompatible drug delivery systems we need to understand the physiochemical relationships between the structure of the nanoparticles and their penetration and efficiency and we can use neutrons to do that.”

A bit of heat aids drug release. Nanogels offer temperature sensitive release of drugs through the skin.

The team have been using ISIS to study the ability of their synthesised nanogels to penetrate the skin. The nanogels are made up of cross-linked isopropyl acrylamide (NIPAM) which is thermo responsive, offering the unique characteristic of being able to alter its size, volume occupied and hydrophobic character as a result of changes in temperature of the solution. In order to evaluate its potential for applications as a drug delivery vehicle the team have been using neutron reflectometry and neutron scattering to investigate the interaction of their nanogels with various artificial mimics of the skin composition.

Miss HuiHui Sun, PhD student on the project explains, “Linear NIPAM polymer can respond at a temperature of about 32 degrees, very close to our skin temperature, which is why we chose this material. What’s important is that we can tune the way in which this material responds by varying the concentration of crosslinker in the preparation, so for example at about 5% the transition temperature is around 34  degrees but with 30% cross-linker the transition temperature goes over 40.”

“This is a real benefit because if we have a way of tuning the release it gives you selectivity”, explains Ali, “so it could be active at physiological temperatures but also in the future you could have a patch on the skin with two reservoirs of drugs and by creating a small potential you could deliver a bit of drug. Then when you stop it and the conformation of the nanogel reverses, it would become inactive, until you start heating again.”

Interaction of thermal sensitive nano-gels with stratum corneum lipid monolayer
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 “At the moment we are looking at a series of nanogels which we have synthesised with different cross linkagers”, explains Ali.  “So they’ve got different conformations and different sizes and we are looking at a how viable they are in terms of penetrating the cell membrane. So we have for example a monolayer on the surface of cell water and also we’ve got it in terms of a stack of multilayers which mimic the structure of the skin more closely.  Then we inject the nanogel, change the temperature and we drive it through these multilayers to see how far they can penetrate and evaluate, for example, the need for an enhancer to improve the penetration and what conditions can we optimise to do that.”

The neutron data gives an understanding of how the nanogel is penetrating the skin, and allows to study the cell transport properties and the selectivity of the membranes. The team are looking at the composition of the idealised skin membranes and also the individual components and how they interact in order to better understand the transport.

“If we can understand transdermal transport on a molecular level then we can extend the range of drugs that can be delivered safely and efficiently. This will extend patient choice acceptability and compliance in drug administration”

The team are also currently looking at the cytotoxicity and cell internalisation of these nano-gels in skin cells as well as preliminary work on their penetration on excised human skin. The next stage of the project will be to look at drug uploading of the nano-gels and evaluation of the effect of the drug on the penetration of the skin.

Felice Laake

Research date: May 2014

Further Information

NIPAM:N-isopropyl acrylamide

For further information please contact Dr Ali Zarbakhsh

References

Mark R. Prausnitz, Robert Langer. 2008. Transdermal drug delivery. Nat Biotechnol. 26(11): 1261–1268. doi:10.1038/nbt.1504​