Smuggling drugs into the brain: old and new tricks


Figure 1. Proposed mechanisms of transport across the blood-brain barrier

Every medicinal chemist involved in neuroscience drug discovery has experienced the joys and pains of the blood brain barrier (BBB), classically defined as the system of tight junctions between the epithelial cells of the brain capillaries that strictly regiment the access of molecules into the CNS.

As medicinal chemists, we usually picture the BBB as a more impenetrable version of other biological interfaces and consequently we design our CNS-penetrant molecules applying more rigid physicochemical filters. Additionally, we use in vitro brain permeability models that tend to focus only on passive diffusion and efflux.

In reality big and polar molecules, antibodies and viruses have the ability of crossing or eluding the BBB using a number of ‘side entrances’.

In the last 30 years the understanding of the BBB mechanisms has increasingly gained clarity and accordingly many new opportunities for drug delivery into the brain have been tested. These new opportunities usually exploit existing mechanisms utilised by endogenous molecules that need to gain access to the brain (e.g. nutrients, aminoacids, regulatory blood proteins) or tricks invented by pathogens. Old and new ways of crossing the BBB have been recently reviewed by William A. Bank in the April issue of Nature Reviews Drug Discovery (doi:10.1038/nrd.2015.21).

Some of the most interesting and overlooked pathways include:

Access via influx (blood-to-brain) transporters – this is an old strategy for drug delivery (e.g. L-dopa, gabapentin which use transporters for neutral aminoacids). More recently this mechanism has been considered for selective delivery to targeted areas of the brain.

‘Trojan Horse strategies  –  where a therapeutic agent (cargo) is conjugated to a ligand (Trojan Horse) of a particular influx transporter expressed on the luminal membrane (blood-side). The complex in usually routed on the abluminal membrane (brain-side) by transcytosis.

Absorptive transcytosis – another vesicle-based pathway often used by penetrating peptides and antibodies fragments.

Extracellular pathways or functional leaks – these are anatomically defined areas of the brain that are deficient in blood brain barrier and as such allow controlled access to small amount of serum proteins including albumin and immunoglobulins. It has been suggested that antibodies – with low volume of distribution and high circulating half-life – can enter the CNS using this way.

Many small molecules and biologics that exploit these or similar tricks are being validated in the clinic.

Nevertheless, these mechanisms are quite difficult to predict and permeability models available to medicinal chemists for rational design are unfortunately still very rudimental…


Figure 1 adapted from: Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier; Julia V. Georgieva et al. Pharmaceutics 2014, 6, 557-583; doi:10.3390/pharmaceutics6040557


Blog written by Alessandro Mazzacani


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