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June 2002
Vol. 5, No. 6, pp 22–24, 27.
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Focus: Therapeutics
Feature Article

Breaching the blood-brain barrier


Researchers are developing tactics to deliver therapeutics to the well-guarded "ruler of the Organs".

opening artIn the fortress of the human body, the brain is the powerful, complex, and fragile ruler of the organs, transmitting its decrees from a highly secured region. Not only is it sheltered from outside forces by the skull, but there is also an effective security system made of tightly wedged cells, called the blood–brain barrier, or BBB, that closely oversees what enters the brain from the rest of the body. The BBB allows only required elements, such as nutrients and proteins used by the brain, to enter the brain’s capillaries, turning myriad other bloodborne molecules away.

And yet, in its task of protecting the chemistry of the brain, the BBB also betrays it by barricading many compounds that might help in diagnosis or treatment. According to a recent article in Nature Reviews: Drug Discovery by William Pardridge from the University of California, Los Angeles (UCLA), School of Medicine, “The BBB prevents the brain uptake of >98% of all potential neurotherapeutics” (1). In addition, the inaccessibility of the brain is a major contributing factor to the common failure of chemotherapies for brain tumors. These problems have led researchers to mastermind drug delivery rescue missions that aim to smuggle new medicines past the well-guarded gates of the central nervous system (CNS) to aid the ailing organ.

BBB blueprint
Planning any successful aid mission first requires a full briefing on the obstacles that will be encountered.

The capillary endothelial cells that make up the BBB form very tight, high-resistance junctions that line the blood vessels that run through the brain. They act as a continuous lipid blockade, preventing the free diffusion through extracellular pathways that occurs regularly at most other organs. For a molecule to diffuse through the BBB, it must have a sufficient amount of lipid solubility. In addition, the larger it is, the more difficult diffusion will be (no matter its solubility characteristics).

However, highly lipophilic, small molecules cannot fulfill all the needs of a functioning brain. Small polar molecules, such as glucose and amino acids, and larger proteins, like insulin and transferrin, are also vital to the workings of the brain. These types of compounds must use more refined “gatekeeping” processes to become part of the blood–brain chemical traffic. Each of the required small molecules has its own transporter proteins expressed at the BBB that whisk it through the cell membranes in a process called carrier-mediated transport. For proteins, specific BBB receptors bind the large molecules and pull them across the barrier in a mechanism called receptor-mediated transcytosis. In addition, some ionic proteins (e.g., cationic albumin) bind to and penetrate the BBB using electrostatic interactions, in a process called absorptive-mediated transcytosis.

One line of attack to get needed drugs to the brain is to (chemically) storm the BBB to break down its walls. The situation, of course, is sensitive, because wiping out the BBB’s defenses would let in not only therapeutic drugs but also many other blood borne molecules that are dangerous to the nervous system. Thus, although complete obliteration is not a satisfactory option, systems have been devised for temporary disruption.

One such approach, osmotic disruption, uses a concentrated dose of mannitol, a sugar alcohol, to remove fluid from the brain’s endothelial cells, which causes them to shrink and the tight junctions to open. This method has already been approved and used to supplement chemotherapy for certain patients with brain tumors. Another strategy for temporary BBB disruption involves exploiting some weaknesses that occur in the BBB at tumor locations (the blood–tumor barrier, BTB). The BTB tends to become “leakier” than the rest of the BBB (but still impassable by many drugs) because of a greater sensitivity to molecules that cause vascular dilation in brain blood vessels. This leakiness has been shown to increase with the injection of an analogue to one of these vasodilators, called RMP-7, and to enhance chemotherapy delivery to the brain. This approach, which has demonstrated increased brain delivery of carboplatin in rat studies, is targeted directly at the tumor and has been shown to “open and close” the BBB more rapidly than the osmotic approach. In either case, though, barrier disruption is still considered somewhat risky, particularly for therapies required regularly over a long term.

Master of disguise
Other BBB strategies follow more covert means of overtaking disease in the brain—sneaking through the natural pathways that already exist. Free diffusion of lipophilic molecules is one such pathway. All brain-targeting therapies currently in use employ molecules that are small enough and lipid-soluble enough to slip through the BBB in pharmacologically significant amounts. Synthesizing drugs to fulfill this condition is, of course, a means of solving the BBB problem, but it eliminates vast numbers of potentially useful polar molecules from the ranks.

A powerful tactic for taking advantage of the diffusion pathway for more general use is being developed by researchers led by Nicholas Bodor at the Center for Drug Discovery at the University of Florida. Using the “master of disguise” strategy, they have come up with a chemical delivery system that shepherds hydrophilic neuropeptides, which offer a wide range of potential therapeutic applications, through the BBB.

By cloaking the polar ends of the peptides with lipophilic groups, the drugs take on a new “lipidized” identity that allows unimpeded diffusion into the brain capillaries. The system is constructed in such a manner as to take advantage of the natural enzymatic processes of the CNS, so that the disguised drug gets locked into the brain and releases the active molecule to fulfill its duties (see Figure 1).

Figure 1
Figure 1. Secret agent med. The analgesic leucine–enkephalin analogue (shaded) is attached to 1,4-dihydrotrigonellyl, via amino acid spacer groups, on the N-terminus and a bulky lipophilic ester (Lpf) on the C-terminus to “disguise” the peptide’s polarity. Oxidation of 1,4-dihydrotrigonellyl locks the compound into the BBB, and further enzymatic processes in the CNS release the active peptide. The ionic molecule that remains in the bloodstream is readily eliminated. (Adapted from J. Med. Chem. 1996, 39, 4775–4782.)

Bodor and his colleagues have shown that by fine-tuning the length of the amino acid spacers used to connect the lipophilic modifiers, the enzyme chemistry can be adjusted to favor the “lock-in and release” chain of events. They have demonstrated brain drug targeting in mice for several peptides that do not naturally show satisfactory BBB penetration, including two analgesics—a leucine–enkephalin analogue and a kyotorphin analogue—as well as a thyrotropin-releasing hormone analogue, which has potential applications for Alzheimer’s disease, spinal cord trauma, and motor neuron diseases.

Trojan horse tactic
For therapeutic compounds that are not synthetically open to lipophilic modification or are too large for diffusion, other means of blood-to-brain entry have to be explored. Attaching an active drug molecule to a vector that accesses a specific catalyzed transport mechanism creates a Trojan horse-like deception that tricks the BBB into welcoming the drug through its gates.

To fully exploit this approach will require more specialized neuroscience reconnaissance missions, particularly of the genomics and proteomics type, in order to unearth the transporter and receptor terrain of the BBB, much of which is still a mystery. However, work using the transporting systems that are already well known has demonstrated the strong promise of this method.

Figure 2
Figure 2. Trojan horse designs. Two different delivery architectures used for brain drug targeting. (A) Brain-derived neurotrophic factor (BDNF) is linked to a monoclonal antibody (MAb), which binds to the transferrin receptor (TFR) on the BBB, via streptavidin (SA)–biotin chemistry. The BDNF is surrounded by strands of polyethylene glycol (PEGylated), which inhibit the uptake of the drug by peripheral organs, particularly the liver. (B) Double-stranded plasmid DNA is encased in a liposome that is attached to PEGs that bind the MAb transport vector for nonviral brain gene delivery. (Adapted from Nat. Rev.: Drug Discovery 2002, 1, 131–139.)
The receptor-mediated transcytosis pathway has been exploited to deliver large biomolecules, a class of compounds that is almost universally unable to cross the BBB (because of their size and polarity), using vectors that bind to protein-specific BBB receptors. For example, Pardridge’s UCLA laboratory has developed what he calls “molecular Trojan horses” that deliver an array of diagnostics and therapeutics to the brain by using a peptidomimetic monoclonal antibody (MAb) vector that binds specifically to the rat transferrin protein receptor (see Figure 2). In rat studies, they have sneaked in several important molecules, including recombinant brain-derived neutrophic factor, which has neuroprotective activity for strokelike injuries, and radiolabeled amyloid-β for Alzheimer’s diagnosis. By binding plasmid DNA-loaded liposomes to the vector, they have also successfully demonstrated nonviral gene therapy delivery. Moreover, a MAb that binds to human insulin receptors has proved capable of being delivered intravenously to the primate brain (1).

The carrier-mediated transport gateway can be fooled into letting in polar small-molecular-weight drugs. Transporters for nutrients have been studied and exploited for drug delivery by conjugating the nutrient compounds to the drugs of interest. For example, a group of Italian scientists led by Stefano Manfredini recently illustrated the effectiveness of nipecotic acid (which has potential applications to Parkinson’s disease and epilepsy) in inhibiting induced rat convulsions when conjugated to ascorbic acid (which accesses ascorbate transporters), while nipecotic acid alone was ineffective (2).

Small cationic peptides can also be used to take advantage of the electrostatically induced absorptive-mediated transcytosis mechanism. Scientists from Synt:em, a company in Nîmes, France, have demonstrated increased uptake of the anticancer agent doxorubicin, which is often restricted because of the efflux activity of P-glycoprotein. They plan to market this delivery technology for a range of other therapeutics.

Headway, nose way
While the BBB is keeping many researchers occupied, others are raiding the brain on different fronts. One strategy of eluding the barrier outright is to go straight through the skull by injecting or surgically implanting drugs. Of course, this approach is extremely invasive (and expensive). For brain tumors, though, it provides an option for targeted treatment, which reduces side effects from interaction with other organs. In fact, an implantable slow-dissolve polymer wafer called Gliadel, spiked with a chemotherapeutic, has been approved for brain tumor treatment. For a more general approach to brain therapy, however, less invasive tactics are much preferred.

Others think they may have found a completely different therapeutic tunnel to the brain that bypasses the BBB and is noninvasive—through the nose. For some time, it has been known that viruses can make their way to the CNS through the nasal passage. Various work also has shown that cocaine, a drug of abuse that is snorted, exhibits its rapid effects by taking a direct path to the brain. Animal studies in recent years have demonstrated that dropping both small and large therapeutic drugs through the nasal cavity delivers them to the brain, often in only a few minutes (3). If this method could be developed further, it would offer a framework in which to target various neurological conditions without the complexities (and expense) of carrier molecules and their potential to cause side effects while traveling through the bloodstream.

Mission: Mobilize
CNS treatments are a major thrust of research in the pharmaceutical industry and biomedical community, and several important drugs have been brought to market. However, to take advantage of many powerful new brain therapy options that are evolving, most notably the promise of genetically engineered molecules, the walls of the BBB must be reckoned with.

Whether it is through force, deception, or evasion, tactics to outwit the cellular stronghold will need to be implemented in a clinical setting to mobilize therapeutic rescue operations for the millions who currently suffer from the many diseases of the brain.


  1. Pardridge, W. J. Nature Rev.: Drug Discovery 2002, 1, 131–139.
  2. Manfredini, S. J. Med. Chem. 2002, 45, 559–562.
  3. Thorne, R. G. Clin. Pharmacokinet. 2001, 40 (12), 907–946.

David Filmore is an associate editor of Modern Drug Discovery. Send your comments or questions regarding this article to or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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