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Jenny Bryan is a freelance writer based in London
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High-tech wizardry is boosting drug delivery to many parts of the body.
But the brain is proving a formidable adversary for those intent on designing
new medicines to treat central nervous system diseases such as epilepsy,
Alzheimer’s disease, schizophrenia and brain tumours. Specifically,
the endothelial cells that form the capillaries of the brain are in no
hurry to stop acting as the so-called blood-brain barrier (BBB), despite
the ever more ingenious efforts of pharmaceutical scientists to overwhelm
them.
David Begley, who jointly runs the Blood Brain Barrier Research Group
at King’s College London, explains that, in contrast to the open
endothelium of the peripheral circulation, the tight junctions between
the endothelial cells of the brain’s capillaries make it impossible
for anything to get into the brain around the cells. Everything must
go across the endothelial cell, either by passive diffusion or with the
help of transporters, some of which work on the luminal membrane of the
endothelial cell and others on the abluminal membrane which is in contact
with brain cells.1
Traditionally, pharmaceutical companies have chosen uncharged, lipophilic
compounds as CNS drugs because they have the greatest chance of getting
across the BBB. But Dr Begley predicts that a growing understanding of
its function and molecular biology will open the way for new delivery
strategies over the next few years.
Early methods
Early efforts to manipulate the BBB in favour of drug delivery focused
on prising apart the tight junctions between the endothelial cells.
Hypertonic solutions introduced into the circulation via the carotid
artery essentially shock the cells and make them shrink so that the
junctions open up. This provides a window of about 30 minutes during
which a CNS drug can be administered, also through the carotid artery.
But the mechanism is non-specific and, during treatment, the brain
is open to other, potentially toxic, substances in the blood. Novel transport systems
Using the BBB’s own transporters has proved a popular option. Valproic
acid, L-dopa, baclofen and gabapentin all use endogenous transporters.
But considerable effort over the past few years has gone into developing
novel transport systems, such as nanoparticles and liposomes, with or
without monoclonal antibodies as targeting mechanisms.
The greatest success with nanoparticle delivery — some would say
the only success —has been with the anticancer agent, doxorubicin.
Preclinical studies reported earlier this year showed that rats with
glioblastomas had longer survival times when their tumours were treated
with doxorubicin bound to polysorbate-coated nanoparticles, 200–400nm
in diameter, than when they were treated with other formulations of doxorubicin.2
Advectus Life Sciences, based in Vancouver, is collaborating with researchers
at two US universities to perform preclinical and drug stability tests
on Nanocure, its nanoparticle formulation of doxorubicin, and hopes that
it will get “fast track” attention from the Food and Drug
Administration.
Advectus is also investigating the possibility of using its nanotechnology
for drug delivery of the anti-infective agent, dapsone, into the CNS
as a potential treatment for Alzheimer’s disease.
NanoPharm AG, based in Magdeburg, Germany, has close links with the Frankfurt/Moscow
team that carried out the promising rat studies with doxorubicin nanoparticles,
and is looking for partners with which to develop its own Nanodel particles.
But the pharmaceutical industry is sceptical about the potential of nanotechnology
to deliver in CNS diseases. Adam Dudley,
associate director of drug metabolism and pharmacokinetics at AstraZeneca
in Wilmington, US, points out that many companies, including AstraZeneca,
spent several years investigating the potential of nanoparticles and
other novel delivery technologies for CNS drugs.
“Nanoparticles have to be given intravenously and, unless coated
with a surfactant, are cleared quickly by the liver. This makes them a
fairly
inefficient and therefore expensive technology,” he says. Passive diffusion and efflux
Instead of working on novel transport systems to get their drugs into
brain cells, companies with strong CNS research programmes, such as
AstraZeneca and UCB, are using tried and tested methods, like ensuring
adequate passive diffusion rates using synthetic medicinal chemistry,
for getting drugs across the BBB.
“
By using drugs that rely on passive diffusion, we can establish a rapid
equilibrium between plasma and brain levels. This ensures a lower risk
of poor or variable CNS exposure than if we use active transport systems,” he
says.
But the mechanism by which drugs get into the brain is only part of the
story. Dr Dudley explains that, even if a small fraction of a compound
gets across the BBB, a high level of potency and receptor occupancy is
what counts. This is difficult to measure in humans, but biomarkers,
for example in the cerebrospinal fluid, can be checked to ensure that
the right concentration of a drug is getting into the brain to drive
its clinical efficacy.
Having saved their money on high-tech delivery systems, the pharmaceutical
industry is investing in research on the efflux mechanisms in the BBB
that actively eject drugs before they can reach their target. Perhaps
the most important of these is P-glycoprotein — a transporter on
the luminal membrane of endothelial cells in the brain — which
first came to researchers’ attention when they realised that even
some highly lipophilic molecules were not getting across the BBB as easily
as expected.
Intensive research into P-glycoprotein over the past five years has confirmed
its affinity for lipophilic compounds, particularly flat molecules with
amines in their structure, says Dr Dudley. Animal models and cell systems
are now used to screen new compounds to see if they are a substrate for
P-glycoprotein.
“
Some companies stop research on a new compound as soon as they see it
is affected by P-glycoprotein but we prefer to try to modify the structure
to see if we can get it past the efflux mechanisms,” Dr Dudley
explains.
Henrik Klitgaard, director of preclinical CNS research at UCB Pharma
in Brussels, Belgium, agrees that efflux mechanisms are a big issue for
CNS drug research, especially in epilepsy.
“Drug refractory epilepsy is due largely to the fact that most anti-epilepsy
drugs get across the blood-brain barrier but then are actively transported
out by mechanisms like P-glycoprotein,” he says.
In fact, researchers at the Institute of Neurology in London last year
published results of a pharmacogenomic study showing that epilepsy patients
with a specific polymorphism in the P-glycoprotein gene were more likely
to be resistant to anti-epilepsy drugs than patients who did not have
the marker.3
UCB’s own epilepsy drug, levetiracetam, and its follow-up compounds
now in early phase clinical trials, are not targeted by
P-glycoprotein, and this is thought to
account for the relatively low levels of resistance to levetiracetam
seen so far in clinical practice.
Poor efficacy is not the only reason to try to avoid drugs that are targeted
by efflux mechanisms, says Dr Klitgaard: “If you have a compound
that is actively transported out, then you need higher plasma concentrations
to achieve a steady state in the brain, and that is likely to give you
more side effects.”
A number of P-glycoprotein inhibitors have been used in phase I and II
trials of anti-cancer drugs in an effort to improve their efficacy against
brain tumours. But, as with drugs that open up the tight junctions between
endothelial cells, the adverse effects of disturbing the BBB proved greater
than the benefits.
The time for novel drug delivery strategies to the brain will come, say
those actively involved in research, but it is not here yet. References
1. Begley DJ. Understanding and circumventing the blood-brain barrier.
Acta Paediatrica Supplement 2003;443:83–91.
2. Steiniger SC, Kreuter J, Khalansky AS, Skidan IN, Bobruskin AI, Smirnova
ZS et al. Chemotherapy of glioblastoma in rats using doxorubicin-loaded
nanoparticles. International Journal of Cancer 2004;109: 759–67
3. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB,
Wood NW et al. Association of multidrug resistance in epilepsy with a
polymorphism in the drug-transporter gene ABCB1. New England Journal
of Medicine 2003;348:1442–8 |
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