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CNS targeting: Have we travelled in right path?

AD Punitha, AK SrivastavaThursday, December 23, 2010, 08:00 Hrs  [IST]

Now brain disorders and their prevalence are at the rise. CNS targeting, however, is in its infancy state, and the approaches we have taken till today is just a handful. Even at present, it is graspable that molecular weight and lipophilicity are considered to be the foremost factors to take up control over the penetration of molecules through Blood Brain Barrier (BBB). It is where all the academic neurosciences and pharma industries commit mistake i.e. wrong perception about BBB and its originality. They all are after the widely held erroneous statement that molecule of less than 400 Da and of lipophilic nature crosses the BBB and the various approaches handled to target brain itself has confirmed this wrong inclination. Reality of the BBB and obstacles endowed with it has really gone unnoticed. So, this communication takes an opportunity to unveil the limitations of these two basic criteria i.e. molecular weight and lipophilicity towards the extent they could work on brain delivery; to flicker light on the controversies prevail and on the presence of gate-like transport systems viz.  Blood-brain influx transporter, Brain-blood efflux transporter and Active efflux pump in the endothelial cells of BBB.

Why does CNS targeting deserve much attention?
Conglomeration of CNS disorders and their high prevalence deserve much attention to be paid. Kola and Landis have reported in their communication that CNS-acting candidates have the poorest success rate in clinical development and development of more than 98% of such candidates had to be discontinued because of poor permeability across the BBB.
This conglomeration of CNS disorders needs to be treated with disease-curing molecules not with symptom-suppressing molecules. It is not the olden century to discover the drugs through old trial-and-error drug discovery process with least bothering towards their receptor binding ability. Due to the lesser development of neurological disorders, it was found manageable to treat with old fashioned drug candidates i.e. symptom suppresser, molecules of less than 400 Da in molecular weight and of lipophilicity. No more it is quite fine to run behind the chemical-driven process to treat the novelty of brain disorders.
This is the era of biology-driven process and drug molecules are discovered through screening process like receptor-based HTS methodology for its receptor binding ability. Unfortunately nearly all the drugs that come out of receptor-based HTS programs lack the two basic criteria necessary for BBB transport. Due to the high break-through of genomics sciences and gene microarrays, thousands of new large-molecule drug candidates like recombinant proteins, monoclonal antibodies (MAb), short interfering RNA (siRNA), non-viral gene medicines and molecular ‘Trojan horses’ have emerged and proven themselves to be curative molecules. However, the biggest hurdle against the delivery of these disease-curing molecules in to brain is the presence of BBB. Future growth of neuropharmaceutical field lies over the understanding of BBB.
BBB call for its better understanding for the betterment of CNS disorders’ treatment since it is the only object which holds the recent advancements back. BBB symbolizes a formidable obstacle for both macro and micro molecules in CNS targeting even though it is greeted for its neuroprotection. But we often misapprehend this mighty BBB by concluding that this has problem with size and hydrophilicity of drug molecules alone. We were enough bright in realizing its physical barrier i.e. tight junctions but the barrier due to expression of multiple transporters is still remain to comprehend. The anatomical and functional characteristics of the BBB challenge our novel advancement of this field.

Evidence to reset the basic criteria
The hypothesis about lipophilicity and molecular weight has stumbled in many places. For example, penetration of histamine, a small molecule of 111 Da was studied in 1986 by Pardridge through an autoradiogram of whole body of an adult mouse sacrificed 30 min after the intravenous injection of radiolabelled histamine. Despite the small size of this relatively lipid soluble molecule, there is no significant penetration of histamine into the brain or spinal cord, whereas histamine readily had navigated into the porous capillary beds perfusing all organs other than the central nervous system. The observation alone stands sufficient to invalidate those widely held misconception about low molecular weight and lipophilicity.

Cyclosporin A is more lipophilic than diazepam. But diazepam crosses the BBB while cyclosporin couldn’t cross. Majority of anticancer agents like Vinca alkaloids (Vincristine & Vinblastin), Doxorubicin and Epipodophylotoxin are highly lipophilic yet they have never crossed the BBB unless enhanced targeted delivery is employed. Many a times it is just amazing that there are no restrictions for the free movements of essential nutrients such as glucose, amino acids like L-phenylalanine, L-leucine and are regularly transported into the brain even though they are polar in nature. HSR-903, a newly synthesized quinolone antibacterial agent of highly lipophilic nature (the octanol-water partition coefficient at pH 7.4 is 2.58), showed a very limited brain distribution.
Some essential neuropeptides permeate into the brain with the aid of specific carriers. Furthermore, transport of peptides and proteins through the BBB by saturable transport system has been confirmed for cytokines such as MIP –1a and MIP–1ß or interleukin-1a.  Candidate like Dalargin (hexapeptide), kytorphin (dipeptide), loperamide, Tubocurarine, MRZ 2/576 and MRZ 2/596 (NMDA receptor antagonist) and Doxorubicin that normally cannot cross the BBB has been successfully delivered to brain after Coating with apolipoprotein, substrate of LDL receptor. So it is discredit to still be behind the lipophilicity and molecular weight.

The real ways to reach out the brain
Recent progress in BBB research has revealed the presence of multiple transporters of solute transfer across endothelial cells and into the brain interstitium at the BBB, and they influence the BBB permeability of various small and large molecules that are their substrates. With the help of Positron Emission Tomography, the activity of human BBB transport systems in vivo has been evaluated. Proteomic studies have also provided important insights into human BBB function. From these studies it is graspable that the brain microvessel endothelial cells (BMEC) that line cerebral capillaries of the brain vessels has been equipped with 3 different specialized transport mechanisms. One is the blood-to-brain influx transport system that supplies nutrients, including glucose, amino acids and nucleotides, to the brain. The second one is the brain-to-blood efflux transport system that acts to eliminate metabolites and neurotoxic compounds from brain interstitial fluid and the third is the drug efflux pump which pumps the xenobiotics including drug molecules out into the circulating blood that already have reached the brain.

Reason behind the failure of drug delivery to the brain
Lets analysis the actual causes lie behind the failure of drug delivery to the brain. It is the wrong notion about the reality of the BBB and ignorance on the presence of multiple expressions of transporters. It is not that molecular weight and lipophilicity limits the brain targeting but restricted anatomical access of the CNS due to complexities of receptor expression on both cytoplasmic and luminal plasma membrane of BBB and back transport of drugs from the brain to the blood by drug efflux pump.

Conclusion
Molecular weight and lipophilicity alone does not limit the transport of molecules across the BBB. The endothelial cells of the cerebral capillaries maintain a high level of expression of transporters i.e. GATE like transporters that limit the permeability of molecules apart from the influence of molecular weight and lipophilicity. So CNS transportation can only be achieved by incorporating structures that are recognized by the blood-to-brain influx transport systems or structures that are not recognized by the brain-to-blood efflux.
BBB and problems associated with it has been overlooked by both the academic neurosciences and the pharmaceutical industry for many years. It is necessary to discover the variety of receptor expression at the BBB, to understand the molecular basis of transport functions, and to utilize this knowledge during drug development. Still thousand of receptor expression remains to be unveiled.  Let’s help them come forth and be succeeded in this clinically primitive area too. Finally, CNS disorders have clothed themselves with novelty through no. of transformation. But it is aching to say that our way of thinking and move thereof has not yet changed to tackle them well.

(Authors are with Dept. of Pharmaceutics, Institute of Technology
Banaras Hindu University, Varanasi- 221 005).

 
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