The 2000 Harrison Memorial medal was presented to Professor S. S. Davis (Lord
Trent professor of pharmacy, University of Nottingham) at the Conference on
September 13.
 |
| Professor Davis |
In his medal lecture, Professor Davis gave an overview of research he has been
involved with over the past 25 years at Nottingham in the area of drug targeting
and use of colloidal carriers (which nowadays, he said, would be called nanotechnology).
When he first started this work, liver uptake of small particles was a major
barrier to drug targeting. If a colloidal carrier loaded with drug was injected
intravenously, the particles quickly became coated with plasma proteins (opsonisation).
They were then recognised as foreign and were removed rapidly by the Kupffer
cells (macrophages) in the liver.
The question was how to avoid the reticuloendothelial system (RES) to allow
targeting to specific sites. “To cut a long story short, we found that
if we make the surface hydrophilic, by attachment of polymers, particularly
polyethylene glycol, we can create a steric barrier to protein adsorption.”
In this way, it was possible to reduce protein uptake, and the particles were
then less likely to be recognised as foreign.
This concept of changing surface characteristics to escape the RES and so produce
“long circulating” particles, which had been commercialised as Stealth
liposomes, led to a number of targeting opportunities, eg, to tumour sites,
for treating infection, or for delivery to sites of inflammation. Furthermore,
ligands (eg, sugars and monoclonal antibodies) might be attached to give more
specific targeting.
Professor Davis moved on to discuss how the physicochemical properties of colloidal
particles could be controlled to meet drug targeting goals. Size and structure,
surface charge and surface hydrophobicity were all important and a variety of
modern techniques could be applied to characterise the particles.
Different types of particles could be used, including liposomes, microspheres
and emulsions, and also self-assembling systems. These were micellar-like systems
where the particles had a solid-like hydrophobic PLA core containing the entrapped
drug and a liquid-like hydrophilic PEG corona. Describing in vivo studies with
the particles, Professor Davis said that it had been possible to target to specific
sites but it did seem that the amount of drug that was delivered was disappointingly
small. This was perhaps not surprising, he said, since the small particle size
made it hard to entrap high drug loads. More recent data showed that loading
of some drugs might be increased by adding another polymer (poly[aspartic acid]).
At Nottingham, they were also interested in targeting to the lymphatic system,
as this had potential use in diagnosis, in drug therapy for cancer and HIV infection,
and for vaccines. The aim was to develop a way of delivering nanoparticles from
an injection site (usually subcutaneous) to the regional lymph nodes.
Particle size was crucial for successful lymph node targeting: if too big they
did not leave the injection site or they left it slowly and did not concentrate
in lymph nodes. A size of 30nm was optimal. However, these were hard to make
and load with drug and so they had compromised on 60nm. Particle coating was
also important — particles had to be neither too hydrophobic (which would
prevent removal from the subcutaneous injection site) nor too hydrophilic (which
would allow them to avoid the macrophages in lymph nodes and so pass into the
circulation). If the balance was right, high uptake into lymph nodes was possible.
They were working with a self-assembling nanoparticle system which gave around
20 per cent delivery to the regional lymph nodes within two hours.
Professor Davis finally discussed how they were now trying to apply the nanotechnology
concepts learnt over the years to delivery of DNA. They were concentrating on
ways of compacting plasmid DNA so that it had the right properties for recognition
and uptake. The nanoparticulate system that they had produced was essentially
a self-assembling system involving anionic DNA and cationic polymer, to which
PEG could, if required, be attached. (PEG acted as a stop mechanism to stop
particles getting too big.) A variety of polymers could be used. At Nottingham
they favoured chitosan — despite what some people said, chitosan was non-toxic,
Professor Davis emphasised. A complex of DNA with chitosan produced particles
of around 90nm. The particles were positively charged as this had been found
to increase stability and transfection efficiency.
One of their areas of interest was mucosal vaccination, in the gastrointestinal
tract or the nasal cavity. Professor Davis said that they were encouraged by
a recent animal study in which a particulate DNA influenza vaccine, expressing
haemagglutinin and nucleoprotein antigens, produced a good immune response,
both in terms of IgG and IgA, after intranasal administration.
Vaccines against respiratory syncytial virus were also being investigated.