Drug Delivery to the Brain

Blood-brain barrier

The human brain is well protected. It is not only shielded from outside impacts by the skull, but also has a protective system on the inside: the blood-brain barrier. The blood-brain barrier between the blood circulation and the brain acts as the biological equivalent of a computer firewall: it selectively allows nutrients and oxygen into the brain, while keeping out harmful components. 

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.


This function results from a combination of:

  • A physical barrier: specialized connections (tight junctions) between cells reduce flux through the intercellular cleft or via the paracellular pathway;
  • A transport barrier: specific transport mechanisms mediate solute flux; and
  • A metabolic barrier: enzymes metabolize molecules in transit.

Physically, the blood-brain barrier is 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 approximately 600 km and has a surface area of about 20 m2. This means that almost every single neuron is perfused by its own capillary.

Although it is crucial in protecting the brain from toxic agents, the blood-brain barrier also blocks entry of most drugs into the brain, with more than 95% of drugs never reaching the brain in therapeutically relevant concentrations. This poses major difficulties for successful CNS drug development.

Enhancing drug delivery to the brain

Several approaches for direct drug delivery to the brain are currently under investigation, including direct single or continuous injections into the brain, cerebrospinal fluid or intranasal delivery. Most of these approaches have major disadvantages such as being too local, short lasting, highly invasive or, most importantly, not safe enough.

In contrast, the vascular route is a very promising approach for drug delivery to the brain as it allows for a widespread diffusion of the infused drug throughout the entire brain due to the large surface area of the human blood-brain barrier. Roughly, two concepts have been described in the literature to actively enhance drug delivery from the blood into the brain: temporary disruption of the blood-brain barrier or the use of endogenous transporters. Several methods are being developed based on disrupting the blood-brain barrier by osmotic imbalance or vasoactive compounds. These methods all carry the risk of temporarily or permanently damaging both blood-brain barrier and neurons due to unwanted blood components entering the brain. Therefore, physiological strategies to use endogenous transport mechanisms are preferable and have a large potential because of the inherent safety aspects of the targeted transport mechanism. This benefit is dependent on the endogenous function of the transporter and its endogenous ligand(s) not being impacted by the technology.

2-BBB leverages its G-Technology® to develop novel therapies involving an endogenous uptake mechanism, without interfering with its function.