9th United Kingdom-Ireland Controlled Release Society Symposium on:
"Access of therapeutics to the brain"

The 9th Annual Symposium of the UKICRS took place in January 2003, with the theme “Access of therapeutics to the brain”. The symposium covered biological aspects of brain delivery as well as formulation challenges and opportunities.

Professor Ivan Lieberburg (Elan Corporation) illustrated the importance of understanding the biology of the target site in his presentation about amyloid protein as a drug discovery target in the treatment of Alzheimer’s disease. Amyloid precursor protein is broken down into beta amyloid, thought to be the main cause of Alzheimer’s disease, by the action of beta and gamma secretases. Elan now have oligopeptide inhibitors of beta secretase with nanomolar specificity in development, with clinical studies predicted to take place in 2004. Gamma secretase has been more complicated as a target site and clinical studies are still some way off. Another approach to the treatment is that of immunotherapy. Active immunotherapy using beta amyloid worked well in pre-clinical studies, but the Phase I human studies were stopped as some patients showed meningo-encephalitis. This was thought to be due to activation of T cells, with the activity directed against the C terminus of the beta amyloid. Clinical studies are currently on hold, but in the future, smaller fragments of beta amyloid may be used to reduce or eliminate this issue.

Dr John Kirk (Queen’s University Belfast) described the role of the blood brain barrier in health and disease using multiple sclerosis (MS) as an example. In MS nerve sheaths are demyelinated and the integrity of the blood brain barrier is affected, resulting in a loss of function and progressive disability of the patient. Dr Kirk described studies using confocal microscopy and immunofluorescence on autopsy samples of MS sufferers to elucidate the molecular basis of the blood brain barrier’s dysfunction. Tight junction abnormality was found in 42% of active lesions, 23% of inactive lesions and 13% in normal-appearing white matter, suggesting that there may be a pre-clinical phase of the disease before the patient realises that something is wrong. He also discussed current therapy for MS, outlining how intravenous steroids may reduce inflammation during acute episodes and how immuno-modulatory drugs, such as beta interferon, may slow progression of the disease, but concluded that there were no therapies currently available which prevent progression of the disease or restore lost function, highlighting the necessity for future research in this area.

Professor Lisbeth Illum (IDentity) discussed the biological aspects of brain delivery via the intra-nasal route. Following nasal application, the drug is likely to be quickly absorbed across the extracellular route into the cerebro-spinal fluid or the olfactory lobes of the brain, resulting in speedy onset of action, although some slower intracellular absorption routes may also be important. Typical brain bioavailabilities, however, are very low and are typically less than 1%. Differences in rat and human physiology were described, such as nasal cavity size and orientation of the head, which affects uptake of nasally-administered drugs to the cerebro-spinal fluid. In general, the uptake of these drugs into the rat brain is greater than into the human brain and this must be borne in mind when analysing pre-clinical studies. Professor Illum reviewed some of the formulation approaches used in attempting to improve drug delivery to the brain via the nose, such as the use of bioadhesive chitosan formulations, and concluded that there are still many formulation challenges and opportunities for this route of drug administration.

Dr David Begley (King’s College London) gave an informative review about the location of and role of efflux transporters in the blood-brain barrier and how their action can affect the delivery of drugs to the brain. Several efflux transporters have been identified as being active in the blood-brain barrier, for example, P-glycoprotein (PGP), multi-drug resistance protein (MDR) and breast cancer resistance protein (BCRP), which, interestingly, appears to be one half of PGP, raising the question of whether it needs to be dimerised for biological activity. PGP itself was described as possibly acting via recognition of a disturbance in the membrane, caused by the presence of a foreign molecule such as a drug, and acting to fix it, rather than by recognising specific molecules, which may help in explaining the wide range of substrates of PGP. Importantly, Dr Begley described how the expression of PGP may change in disease states such as cancer or AIDS, indicating the need for appropriate models to be developed when designing formulations and therapeutic regimens for these conditions.

Dr Wolfgang Staddler (University of Graz) discussed stereometabolism in an in vitro model of the blood brain barrier. In particular he described the roles of ABC A1 and SR-B1 during oxy-sterol transport through the capillary endothelial cells of the blood brain barrier. ABC A1 mediates lipid trafficking via exocytosis on the surface on cells and also retroendocytosis during intracellular processing. SR B1 is primarily expressed in the liver, but also in the brain, and has been reported to be co-localised with caveolae in porcine brain, with caveolae also being involved in signalling. Dr Staddler used as an example the metabolism of cholesterol. In the brain cholesterol is metabolised to 24-hydroxycholesterol, which can then cross the blood-brain barrier and circulate to the liver and bile. It in unclear whether cholesterol itself can cross from the brain into the blood. This type of specific cellular trafficking may have implications for the fate of therapeutic molecules in the brain, if they are substrates for such systems.

Professor David Rees (Synt:em) described his company’s exciting new formulation strategy to transport drug across biological membranes, including the blood-brain barrier. The “Pep:trans” system is derived from protegrin, a mammalian peptide. This “Pep:trans” system can interact with mammalian cell membranes, creating pores, thus allowing the inward diffusion of the drug molecule. The two advantages of this system are that it may interact with the cells without causing lysis, ie barrier integrity is maintained, and also that it bypasses MDR/ PGP, thus maximising the effective dose of the drug. Several examples of the use of this system with various drug molecules were described. An opioid drug was shown to have improved pharmacological activity including fast onset of pain relief; an increased cytotoxic T-cell response was observed after vaccination with protein antigens; the efficacy of paclitaxel in treating brain cancer was increased with no peripheral side effects being observed.

Professor Jörg Kreuter (J.W. Goethe-Universität) described the use of nanoparticles for the transport of drugs to the brain following intravenous injection. In particular, his group have studied the use of drug-loaded cyanoacrylate nanoparticles coated with polysorbate 80 (Tween 80), a widely-used surfactant. A range of drug molecules have shown increased effectiveness when administered in this way, such as the hexapeptide dalargin, the dipeptide kytorphin and the large molecule tubocurarine. Comparative studies with the drug administered either alone, in uncoated nanoparticles or in solution with Tween 80 showed no effect, indicating that for optimal effect, all three components were required, ie the drug-loaded nanoparticles needed to be coated with the Tween 80. The mode of action of the Tween 80 in increasing the brain absorption is not fully elucidated yet, but is thought to be related to the coating of the iv-injected nanoparticles with apoprotein E or B, followed by interaction with the low density lipoprotein receptor, leading to endocytic uptake.

Dr Sylvia Wissing (Freie Universität, Berlin) also discussed the use of nanoparticulates in targetting the brain. She reviewed the use of drug nanocrystals (essentially very fine drug particles stabilised with a surfactant), solid lipid nanoparticles (SLN), nano-lipid crystals (NLC) and lipid-drug conjugate nanoparticles (LDC). Nanocrystals tend to be captured by macrophages after administration, which may not be desirable depending on the intended target site. SLN and NLC are both produced using an oil in water emulsion process, utilising solid lipids and a mixture of solid and liquid lipids respectively. The solid system resulted in a good quality “wall” but lower drug loading, whereas inclusion of a liquid phase resulted in a less well structured “wall”, thus allowing greater drug inclusion. NLC is a newer formulation which has been reported to have a drug carrying capacity of up to 50% of a lipid-soluble drug. All these systems can be prepared using conventional processing techniques in large quantities, obviously an advantage to the pharmaceutical industry.

Taken together, it was a very informative day with an appropriate balance between the biological aspects of brain delivery and the formulations challenges posed thereby. The conference was well-attended, even on a cold wet day in Belfast, and the delegates expressed uniform appreciation of the programme. Along with many of my colleagues, I am looking forward to the next UKICRS meeting.