The Brain’s Drug Delivery Challenge

What is the blood-brain barrier?

The blood-brain barrier (BBB) separates the blood circulating through our bodies from the central nervous system (CNS), which includes the brain. This acts as a control, ensuring that substances that are needed for healthy brain function, such as glucose, amino acids and electrolytes, are present in appropriate levels. It also protects our brain from harmful substances in the blood, such as disease-causing bacteria and toxins.

So how does it do this? Like blood vessels in the rest of the body, those in the CNS are lined with a thin layer of so-called endothelial cells, which are in direct contact with the blood inside the vessels. But CNS blood vessels differ in that their endothelial cells are packed tightly side by side, with their membranes zipped together by specialised protein structures that form tight junctions. These restrict the flow of substances from the blood to the CNS, allowing only small molecules such as water, some gases, and compounds that can pass unaided through cell membranes (called lipid-soluble molecules) to pass freely into the brain.

The membranes also contain efflux pumps, which kick potentially harmful compounds and drugs back out of the brain. Other channels, transporters and receptors in the membranes help essential nutrients and molecules get into the brain.

CNS blood vessels are also surrounded by a lot more supporting cells (pericytes) than blood vessels found elsewhere in the body. In addition they are surrounded by neural cells called astrocytes. The pericytes and astrocytes provide an extra barrier and influence the expression of genes that play a role in the selectivity of the BBB.

You can see that the BBB is not just a simple barrier, but rather a sophisticated and carefully managed border control mechanism.

Illustration by Rick Kollath; kollathdesign.com

What can we do about it?

Thankfully, more and more researchers and clinicians are now trying to address the blood-brain barrier (BBB) challenge, and a range of drug delivery systems and drug delivery routes are being explored.

Procedures that bypass the BBB by local injection of drug into brain tissue (interstitial) or into cerebral-spinal fluid (intraCSF) using catheters have been in use since the 1990s. A more recent development involves the surgical insertion of a catheter into the brain, coupled with drug delivery under a constant pressure gradient (convection enhanced delivery). Other delivery routes include intravenous, intra-arterial and intranasal methods, as well as the placement of drug-containing polymers at the tumour site during surgery.

A whole other area of investigation is focused on ways to temporarily disrupt the BBB whilst drugs are delivered into the brain. Methods under investigation to create this disruption include the use of ultrasound, heating (hyperthermia), osmotic pressure, electromagnetic radiation and biochemical agents such as cyclodextrin.

On a parallel with these ‘routes’ to delivery, numerous drug delivery systems are also being investigated for their potential to ferry therapeutic cargo across the BBB. These include antibodies, viruses, nanoparticles, liposomes and polymeric micelles. Some of these cross the BBB unaided; others work via the ‘Trojan horse’ approach. This involves modifying the delivery system or ‘vector’ so that it can attach to a transporter in the brain endothelial cell membrane. This transporter then carries the vector, and its therapeutic cargo, across the BBB and into the brain. Nanoparticles, for example, have been decorated with glutathione, enabling their BBB passage via the glutathione transporter.

Our own immune cells can cross the BBB unaided, and researchers are keen to explore their potential as drug delivery systems. We have already seen promising research showing that immune cells can be used to deliver drugs into the brain, whether the drug is inside the immune cell (e.g. immune cells harbouring drug-containing liposomes) or attached to it (e.g. antibodies used to link drug-containing polymers to immune cells).

The power of our immune system has also been harnessed indirectly, with promising results from a small clinical trial in the UK recently hitting the headlines. A naturally occurring virus that can cause mild flu-like symptoms – reovirus – was injected into the patients’ bloodstream. The virus managed to cross the BBB and infect the brain tumour cells, which in turn triggered the patients’ own immune systems to mount an attack on the reovirus-containing tumour.

Posted with permission, © Johns Hopkins University Neurosurgery – Ian Suk. All rights reserved.