Leaving the syringe, you are expelled past the deltoid and into a vein, down which you travel through the blood stream. Bumping shoulders with red blood cells, platelets and white blood cells, you navigate the blood plasma seeking your target, all the time avoiding being eaten by macrophages (the primary immune system) and protecting your cargo. Upon arrival, you squeeze and eject this bio-active material which binds to, and destroys, mutant cells. All healthy tissue remains unaffected! A seemingly futuristic hypothesis? Well, the advent of nano-technologies could soon realise this dream.

Targeted drug delivery has the possibility of treating only diseased tissue compared to radiology which can have a negative side effect on healthy organs. The challenge, however, is how best to deliver a drug, such as a DNA fragment used in gene therapy, to an unhealthy organ. One possible solution is to base a transport system around a biocompatible polymer.

A team from the University of Rome Tor Vergata (Professor Gaio Paradossi, Dr Ester Chiessi, Dr Shivkumar Ghugare, Dr Anka Mateescu and Mr. Sharad Pasale), working in collaboration with ISIS scientists (Dr Mark Telling and Dr Victoria García Sakai), is using neutron scattering to study the efficacy of constructing such drug delivery vehicles from bio-compatible polymers.  

The resulting construct is known as a hydrogel or microgel depending upon size, the latter referring to micro/nano sized (roughly) spherical particles. Both, however, are made by cross-linking the polymer chains in such a way that a lattice is formed. When imagined in three dimensions this lattice network can be thought of as plastic ‘sponge’, full of small holes. One bio-compatible polymer currently showing promise for such assemblies is poly(vinyl alcohol), a  material already used for stitches in surgery due to its thermal stability and tolerance to pH changes in our skin.

 

The hydrogel material resembles a plastic 'sponge' in that it is a lattice made up of cross-linking polymer chains. View full-size image

When immersed in water, a hydrogel or microgel will swell and retain up to 99% of its weight in water once removed. Such behaviour has important implications since any bio-active cargo will need to be held in solution within the gel’s pores. This, however, poses questions. How does the water, and hence the bio-active cargo, move in, out and around the gel? Can it diffuse freely through the pores, or is it trapped? Neutron scattering, in particular the technique of quasi-elastic neutron scattering, is being used to answer such enquiry.

When asked, “Why neutrons?” Mark answered, “Quite simply it’s because of the high neutron scattering cross-section of the hydrogen atom. Here we have a material which when immersed in water will largely consist of water molecules, thus hydrogen atoms, since a gel retains up to 99% its weight in water. Neutrons are strongly scattered by the hydrogen atom and the actual scattering process itself is sensitive to how the hydrogen atom is moving.”

Mark went on to add, “What we can do is play games. For example, by systematically changing the number of cross-linked polymer chains, we can see how pore size or gel rigidity impacts on the movement, or diffusion, of the water contained within the material. Another trick is to dip the gel in deuterium oxide, or D₂O, instead of water (H₂O). Since the isotope deuterium has a very small scattering response compared to hydrogen the neutrons hardly notice it. Instead, the neutron ‘sees’ only motion associated with the hydrogen atoms on the polymer chains. Replacing hydrogen atoms with deuterium atoms to make certain parts of a material invisible to neutrons is a process called selective deuteration.  By first looking at the water dynamics using H₂O, then the motion of the gel’s polymer chains  using D₂O, we can fit the results  together like a puzzle to see how the whole system behaves.”

Initial studies revealed that the water molecules bind to the polymer before breaking away and diffusing, the rate at which the water diffuses in the gel pores being cross-link dependant. Such results will have a direct impact on the fabrication of future hydrogel/microgel materials where the diffusive properties of the solvent needs to be tuned. But how would the gel material squeeze and release its cargo? The answer – add a small percentage of N-isopropyl acrylamide which contracts when the temperature rises above 33^oC thus reducing the overall volume of the gel. Neutrons have successfully demonstrated that water is indeed released when the temperature of an acrylamide impregnated gel is raised. Other research avenues currently being explored  include how to intentionally degrade the gel once the drug has been delivered, the gel having to be broken down before entering the lymphatic system and leaving the body as waste. To achieve this, the team have also incorporated polymer-eating enzymes into the gel's architecture.

What about the future? When will such systems be ready for human trial? “It is still very early days”, say Mark. “I see the future fraught with trial and error, many more neutron studies and a lot of inter-disciplinary research still needed to be done. However, our work demonstrates proof-of-concept and the potential for this type of drug delivery vehicle is very exciting.”

Mark Telling and Emily Mobley

 

A team from the University of Rome Tor Vergata are working in collaboration with ISIS scientists to study, using neutrons, the efficacy of constructing drug delivery vehicles from bio-compatible polymers.

Mark Telling et al.

Research date: November 2012

Further Information

For further information, please visit the group's website: http://www.stc.uniroma2.it/cfmacro/cfmacroindex.htm

References:

1.            Ghugare S. V., Chiessi E., Telling MTF., Deriu A., Gerelli Y., Wuttke J., Paradossi G. “Structure and Dynamics of a Thermoresponsive Microgel around Its Volume Phase Transition Temperature", J. Physical Chemistry – B, 2010, 114, 10285.

2.            Ghugare S. V., Chiessi E., Cerroni B., Telling MTF., Sakai V., Paradossi G. “Biodegradable dextran based microgels: a study on network associated water diffusion and enzymatic degradation " Soft Matter, 2012, 8, 2494.