Nanoparticles doped with molecules derived from a neurotransmitter can smuggle chemical cargoes across the blood–brain barrier (BBB). A team at Tufts University in the US created such nanoparticles and used them to deliver a diverse range of therapeutic substances into the brains of mice. The technique could one day be used to treat neurological conditions such as infections and neurodegenerative disorders, while avoiding the side effects that accompany other methods for penetrating the BBB.
The BBB comprises a layer of endothelial cells that line the brain’s blood vessels. This layer of cells is selectively permeable and protects the brain from toxins and pathogens that might be circulating in the blood. Unfortunately, it also keeps out most drugs and other therapeutics, making certain brain diseases difficult to treat by conventional methods of drug delivery.
Finding ways to breach or circumvent the BBB is the subject of active research. Although some techniques have been shown to deliver drugs with a degree of success, methods that disrupt the barrier by chemical or physical means can simultaneously let other – potentially harmful – substances sneak across alongside the intended molecules. Writing in Science Advances, Feihe Ma, Liu Yang and colleagues report an approach that is more selective.
To develop their technique, the team experimented with three chemicals that are naturally present in the brain: tryptamine, phenethylamine and phenylethanolamine. These neurotransmitters are members of the special class of molecules that can cross the BBB in a process that is thought to occur via active transport (rather than passive diffusion) across the endothelial cells’ membranes.
Ma, Yang and colleagues coupled the functional amines in the neurotransmitters to lipid chains. This created composite molecules (NT–lipidoids) that are hydrophobic at one end and hydrophilic at the other. In an aqueous solution, such amphiphilic molecules bunch together to form spherical particles called micelles that can encapsulate other chemical species within their cores. By using NT–lipidoids in this process, the researchers created nanoparticles with surfaces studded with the neurotransmitter-derived amines.
When they injected NT–lipidoid nanoparticles carrying fluorescent dye into live mice, the researchers found that the tryptamine-derived formulation (NT1) successfully breached the BBB and accumulated in the animals’ brains. The presence of tryptamine on the surfaces of the nanoparticles apparently triggered the transport process that lets the neurotransmitter pass into and through endothelial cells. A mystery that the researchers are currently investigating is why the phenethylamine- and phenylethanolamine-derived formulations failed to achieve the same result.
To test the technique with a more therapeutically relevant cargo, next the team used NT1 nanoparticles to encapsulate amphotericin B, an antifungal drug to which the BBB is usually impermeable. Like the fluorescent dye, this substance was also carried across the BBB successfully. However, the researchers found that the concentration delivered to the animals’ brain tissue was even higher when they added lipidoids that included phenylboronic acid to the mixture. This component makes the lipidoid more soluble in water, thus decreasing the size of the nanoparticles from 800 nm to 100 nm as a result.
For some treatments, merely getting the drug across the BBB is not enough, however. Antisense therapy, for example, could be used to limit production of the tau-protein tangles associated with Alzheimer’s disease, but the antisense oligonucleotides (ASOs) that produce the beneficial effect must penetrate into the neurons themselves. To achieve this, the researchers incorporated into the nanoparticles yet another lipidoid, 306-O12B-3, which they had previously shown could deliver ASOs into cells in the liver. They found that nanoparticles that combined NT1 and 306-O12B-3 lipidoids transported the tau ASOs across both the BBB and the membranes of the neurons, yielding a reduction in tau mRNA.
Blood–brain barrier best breached by small molecules
Although the results are promising, the technique is still some way from the clinic. “More studies and clinical trials, including pharmacokinetics, pharmacodynamics, toxicity etc, will be needed to determine the utility and safety of the technology in humans,” explains corresponding author Qiaobing Xu.
There are also still fundamental questions about the phenomenon at the heart of the work. The ineffectiveness of lipidoids derived from phenethylamine and phenylethanolamine is unexplained, but even the way in which the tryptamine-doped nanoparticles work is unclear. “We think they cross the BBB by way of a transporter-mediated process,” says Xu, “but we don’t know the mechanism exactly.”
