Delivering drugs across the blood–brain barrier is very difficult, but researchers have designed a novel way of achieving this. The drug-carrying nanoparticles are injected directly into the cerebrospinal fluid at the back of the neck, and then the glymphatic system transports the medicine deep into the brain.
In the quest to produce medicines for numerous diseases that affect the brain, doctors repeatedly encounter a major problem: the blood–brain barrier prevents even nanoscale particles from entering the brain.
This problem is enhanced by the fact that some drugs have been shown to be very effective in some brain diseases, but they cannot be transported to the target.
New research shows how to trick the brain’s glymphatic system by injecting nanoparticles directly into the cerebrospinal fluid in the neck to deliver drugs to even the deepest areas of the brain.
The discovery opens up completely new therapeutic possibilities for disorders of the central nervous system for which good treatments do not exist.
“In practice, the blood–brain barrier blocks most biological drugs. Nanoparticles, in contrast, can transport many drugs deep into the brain through the glymphatic system. In this study, we showed both how this can be done and where the nanoparticles end up in the rodent brain when they are administered directly into the cerebrospinal fluid,” explains a researcher behind the study, Tuomas Lilius, Docent, University of Helsinki and University of Copenhagen.
The research, which was mostly carried out at the Center for Translational Neuromedicine of the University of Copenhagen in the laboratory of Maiken Nedergaard, has been published in the Journal of Controlled Release.
Using the brain’s glymphatic system
Nanoparticles have considerable pharmaceutical potential because their structure and effects can be designed to be both safe and effective and because integrating nanoparticles with other drugs can improve drug stability or prolong a drug’s effectiveness.
This also applies to treating people with disorders of the central nervous system – if the nanoparticles can be transported in there.
Tuomas Lilius and colleagues investigated whether injecting radiolabelled gold nanoparticles into the cerebrospinal fluid in the neck of rats could get the nanoparticles to end up deep in the rats’ brains and thereby circumvent the blood–brain barrier.
The idea was that the glymphatic system would assist in transporting the nanoparticles. The glymphatic system is the brain’s waste clearance system, using a system of perivascular channels to eliminate soluble proteins and metabolites from the central nervous system.
“Clinicians already know much about injecting drugs of several types into cerebrospinal fluid in the lower back. However, the lower back is far away from the brain, so how much medicine would actually reach the brain is uncertain. In our study, we monitored nanoparticles we had administered to rats by injection into the cerebrospinal fluid at the back of the neck and thus closer to the brain at a location that is accessible in both rats and humans,” says Tuomas Lilius.
To monitor the nanoparticles, the researchers used single-photon emission computed tomography (SPECT), which acquires multiple 2D images from multiple angles through a gamma camera. The researchers thus monitored the radiolabelled gold nanoparticles, which flowed through the cerebrospinal fluid and around the body – including to the brain.
Tuomas Lilius says that the researchers also gave the rats a hypertonic saline solution in the blood to increase the saline balance towards more salt in the blood flowing to the brain. More salt in the blood reduces the water content in the brain, which in turn increases the flow of cerebrospinal fluid into the brain – including cerebrospinal fluid filled with nanoparticles.
Tuomas Lilius elaborates that nanoparticles flow throughout the body completely unimpeded because they have very little biological activity and therefore do not bind to any targets.
The researchers found that the nanoparticles ended up in the areas of the brain in perivascular spaces that are filled with cerebrospinal fluid.
“This is a revolutionary method of following drugs around the body,” explains Tuomas Lilius.
Nanoparticles can transport drugs into the brain
Tuomas Lilius thinks that the combination of transport of fluid into and around the brain by the glymphatic system in combination with nanoparticles presents a potent new way of viewing drug treatment in the brain.
Tuomas Lilius envisions drugs with small molecules being encapsulated in the nanoparticles. In addition, many types of nanoparticles would be suitable for transporting medicine deep into the brain.
In addition, the study is only the first of its kind, since nanoparticles of different sizes could target different parts of the brain.
“The nanoparticles we used were all 10 nanometres in diameter, but making nanoparticles of different sizes and investigating how to optimally design them to deliver drugs to the brain would be easy,” says Tuomas Lilius.
He adds that the study also revealed that the many nanoparticles reaching the brain do not remain there. After briefly exercising a potential pharmaceutical effect, they are efficiently cleared, which probably means that the glymphatic system removes them from the brain and sends them towards the kidneys so that they can be excreted in the urine instead of remaining in the body indefinitely.
“This may also be an attractive feature for medicine intended for the brain,” concludes Tuomas Lilius.