Brain drug delivery
The human brain is well protected. The skull obviously shields the brain from outside impacts. Not so well known is the protection "on the inside": a barrier is present between the blood circulation and the brain, the so-called blood-brain barrier (often abbreviated as BBB). The barrier is physically located in the endothelial cells of the cerebral capillaries. This capillary bed has impressive dimensions: the total length of capillaries in the human brain is approx. 600 km with a surface area of 20 m2. In fact, almost every neuron is perfused by its own capillary.
The blood-brain barrier is a major hurdle for successful CNS drug development. Many high potential "would-be" CNS drugs (especially biopharmaceuticals) can currently not be made available to the brain because they do not (adequately) cross the blood-brain barrier.
Blood-brain barrier
The blood-brain barrier is a highly sophisticated organ that acts as the biological equivalent of a computer firewall: it selectively allows nutrients into the brain, while keeping out harmful components.
The blood-brain barrier function results from a combination of
- a physical barrier: tight junctions between cells reducing flux via the intercellular cleft or paracellular pathway;
- a transport barrier: specific transport mechanisms mediating solute flux; and
- a metabolic barrier: enzymes metabolizing molecules in transit.
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The blood-brain barrier is not fixed: it is in fact a dynamic barrier that is controlled by intra- and intercellular signaling events among endothelial cells, astrocytes and neurons in the blood-brain barrier, as well as by other cells that are in contact with the barrier.
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Enhancing drug delivery to the brain
Several approaches for direct drug delivery to the brain are currently under investigation, such as direct injections or convection-enhanced delivery into the brain, or cerebrospinal fluid or intranasal delivery. These approaches are usually too local, not safe, highly invasive, short lasting, or a combination of these.
In contrast, the vascular route is a very promising one for drug delivery to the brain as it allows for a widespread diffusion of the infused drug throughout the whole brain due to the large surface area of the human blood-brain barrier. Roughly two methods have been described in the literature to actively enhance drug delivery from the blood to the brain: disruption of the blood-brain barrier by osmotic imbalance or vaso-active compounds, or physiological strategies aiming to use endogenous transport mechanisms. The first method has the disadvantage that the strictly controlled environment required for proper functioning of neurons is challenged and neurons may even become damaged (semi)-permanently due to unwanted blood components entering the brain. The physiological strategies have a large potential because of the inherent safety aspects of the targeted transport mechanism, provided that the endogenous function of the transporter and its endogenous ligand(s) is not influenced by the technology in a major way.
10 key development criteria for safe and efficacious drug delivery to the brain
to-BBB strictly adheres to the 10 key criteria that are anticipated to secure a successful development of CNS-targeted drug delivery systems.
| Targeting the blood-brain barrier | Drug carriers | Drug development from lab to clinic |
| 1. Proven inherently safe receptor biology in humans | 6. No modification of active ingredient | 8. Low costs and straightforward manufacturing |
| 2. Safe ligand, effective for humans | 7. Able to carry various classes of molecules | 9. Activity in all animal models |
| 3. Receptor specific binding | 10. Strong IP protection | |
| 4. Applicable for acute and chronic indications | ||
| 5. Favorable pharmacokinetics | ||
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