Friday, 21 November 2008

'Modelling the Cell' article

What follows is the original text I wrote for an article recently published in Chemistry Review, a magazine published at the University of York, and aimed at A Level Chemistry students. I don;t know an awful lot about pharmacological research really, I just thought I'd have a go at writing something after I did a summer research project on a topic related to that discussed in the article. The only problem is I haven't had time to sort out how to add in the diagrams yet! Watch this space..

Modelling the Cell

Disease is still a serious problem in the 21st century. Statistics now show that one in three people will develop cancer at some point during their lives. Chemists have always played an important role in developing drugs to combat disease and they continue to do so in modern science.

Have you ever considered how easy it is just to swallow a pill to relieve a headache or clear your sinuses? It’s very convenient for us to take drugs orally; imagine if you had to inject a syringe-full of paracetamol into your forehead each time you had a headache! Medicinal chemists have worked long and hard to design drugs which can enter our gut, pass through our cell membranes, dissolve in the blood and arrive at the site of action in large enough concentrations to actually do some good. It’s quite amazing when you think about it. For example, one problem that faces chemists is that the pH of the stomach is generally between about 1 and 3, depending on what’s been eaten recently. Unfortunately, lots of potentially great drugs contain acid-sensitive functional groups; under such highly acidic conditions amine groups will become protonated and esters may be hydrolysed. These are serious problems as the structure, and therefore the activity, of the drug is altered. The job of the medicinal chemist is to find ways of getting round these problems.

Polymer therapeutics

Diseases like cancer and HIV/AIDS present us with fresh challenges and in some cases polymer therapeutics could offer a way forward. Polymer therapeutics comprise a series of medicines where a drug molecule and a polymer are combined. In essence, the advantage of these medicines is that the polymer wraps around a drug molecule and protects it from degradation, such as via the stomach acid we just mentioned. One obvious property of such polymer-drug conjugates is their large size – much larger than standard drug molecules because of the polymer chains wrapped around them – leading to their other, somewhat more fashionable name nanomedicines. It has recently been shown that tumours produce large amounts of permeability factors, (compounds which make the lining of blood vessels more permeable). This essentially means that the blood vessels surrounding a malignant tumour are permeable to nano-sized molecules, whereas those surrounding healthy tissue are not. Polymer-drug conjugates are therefore a promising candidate for new anticancer medicines because they will differentiate between healthy tissue and cancerous tissue. The drug will accumulate at high concentrations at the tumour site, providing a two-fold advantage; it will be more effective in dealing with the tumour and will yield fewer side effects in healthy tissue.

Safe polymers?

Before we begin doling out spoonfuls of polymer to hopeful patients we must, of course, be convinced that the polymers of interest are not toxic to humans! One important way to look at this is to study the interaction of polymers with cell membranes – if the polymers disrupt the membrane, the contents will begin to spill out and the cell will die. Cytotoxicity studies (where the analyte is introduced to a cell culture) are performed by biologists and these are a very realistic way of looking at toxicity of a compound. Cell culture studies often give us simply a ‘yes’ or ‘no’ to questions about toxicity. If we want to understand the biophysical interactions taking place the Langmuir technique can be very useful. It allows us to create a simplified model of cell membranes and investigate which types of molecule have an interaction with them. Using a modelling technique has the advantage that one can control parameters such as pH and see their individual effect on polymer – lipid interactions. So while the Langmuir technique is a simplification (it does not take into account the copious protein channels and other moieties on the cell surface for example) it is an invaluable tool.

In real life, cell membranes are composed of a bi-layer of phospholipid molecules. The Langmuir technique enables chemists to create reasonable model of this; a uniform phospholipid monolayer. The phospholipids are not miscible with water (i.e. they do not mix) because they are amphiphillic. This means their hydrophobic tails stick up out of the water and their hydrophilic heads are aligned side by side in the surface of the water (see box 1). Once the monolayer is stable the polymer is injected through the bottom of the shallow trough into the buffer solution. Troughs are equipped with a special surface pressure sensor, so any changes in surface pressure can be measured. These give us indications about what is happening on a molecular level. For example, if there is an increase in surface pressure it indicates that the polymer is inserting itself into the monolayer, forcing the lipid molecules apart. If we did see an increase in surface pressure, it might lead us to conclude that were the polymer interacting with a real cell, it would be interfering with the cell membrane which could cause irreparable damage. Of course further studies would be needed, but the technique gives us a insightful starting point.

Dendrimers; the next generation of polymer therapeutics

Box 2 shows PEG and PEI two polymers used in drug conjugates at the moment. These are both certified as non-toxic and approved for use in humans. Of course the search for new drugs is on-going and an impressive new candidate for use in polymer therapeutics is a class of compound known as dendrimers. These novel polymers are monodisperse, spherical polymers grown outwards from a central core. Their hollow core area has the potential to act as a protective storage area for drug molecules. Their monodispersity makes them an attractive candidate as a delivery vector too, as it means their action in the body can be more easily and accurately predicted. The functionalised arms however mean that they are likely to have an interesting and novel interaction with cell membranes. The Langmuir technique will be one way in which chemists try to discover the nature of this interaction. if dendrimers are not toxic, we could have the makings of an excellent drug delivery vector.