Associate Professor of Neurobiology Zhi “Elena” Zhang understands why people are often frustrated by the slow pace of development for therapies targeting brain injuries and neurological diseases. After all, we regularly hear news stories about potential game-changing new treatments, and yet effective clinical solutions break through at a much more modest pace.
Zhang says there are a few reasons why treating the brain is particularly challenging — chief among them, the fiercely protective nature of the blood-brain barrier. This complex network of blood vessel cells and tissues selectively allows vital nutrients, like oxygen and glucose, to reach our brains, while turning away pathogens and toxins, and funneling away waste. Unfortunately, pharmaceuticals meant to treat the brain are among the things that have a hard time getting through. “Many of the drugs we’re developing may show promising results when we’re studying them in the lab at the cell or organoid level. But in the human body, the majority of these drugs cannot cross the blood-brain barrier,” Zhang says.
Even drugs designed to traverse the BBB still face challenges. Zhang says today’s drugs are typically unable to target just the parts of the brain that are injured or diseased. Doctors thus have to administer very high doses to ensure enough of the medicine reaches the desired destination. This not only results in flooding healthy parts of the brain with potentially harmful chemicals, it can take a toll on patients' kidneys and livers, which have to work extra hard to clear the body of the excess drugs. Moreover, targeting neurons — the cells vital to transmitting electrical and chemical signals in the central nervous system — is particularly difficult, as there are many different types.
Because of these challenges, researchers like Zhang are trying to create therapeutic approaches that can both cross the BBB and deliver smaller doses of pharmaceuticals to just the places they want them to go. With a new $3.1 million grant from the National Institutes of Health, $1.1 million of which has been allocated to Zhang’s lab, Zhang and her collaborators at Washington State University are testing a novel nanoparticle platform that they hope can do just that.
Owing to their minute size, nanoparticles are an ideal solution for traversing the BBB. But researchers can also attach things — like drugs — to them. “Of course, it’s so much smaller, but you can kind of think of it like a Lego platform,” Zhang explains. “You have this smaller centerpiece and then you can start adding an arm, a head, a helmet, and pretty soon you have a little person. It’s the same thing with this nanoparticle platform. You have a core and then you can start adding branches to it so it can do different things.”
For this particular project, Zhang and the team will primarily be using the nanoparticle vehicle to deliver very small doses of drugs across the BBB to specific neurons that have been damaged following traumatic injury. They can also attach other things, like fluorescent tags, to the vehicle, which help them determine if the packages are reaching their destinations. And how exactly does the nanoparticle vehicle know where to go? Zhang says the platform is equipped with specific design features that only allow it to bind with transporters or receptors on specific neurons, sort of like a lock and key. This is what enables very small, targeted doses to be delivered. Notably, unlike some precision medicines, the selective binding features are built into the platform — not the drug. That means you could theoretically load the vehicle with a wide variety of drugs and other useful tools. “We’re even thinking about whether we could use the platform to assemble multiple drugs that can target multiple individual pathways and work together. So the smart platform could work like a team,” she says. “This could be useful not only for complex drug delivery, but also to deliver imaging tags, so we can see if these drugs are going to the areas we want them to.”
Right now, the work is in a pre-clinical phase, with research focused on the efficacy of the nanoparticle platform to deliver desired doses of drugs to the intended neurons, and the efficacy of the pharmaceuticals themselves in improving outcomes after traumatic brain injury. For this stage of research, mice models are particularly useful, because they have biologies that are quite similar to humans, including having a BBB. And while this particular project is focused on neurons, Zhang says the underlying nanoparticle technology could ultimately be applicable in a variety of contexts. “That’s really the goal,” Zhang says. “Neurons are just one possibility. We have this really nice platform that could potentially be used to target tumors or many other cell types. That’s the dream of personalized or precision medicine.”
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