Apr 1, 2001
by Anton Zuiker
Your brain is a fortress. Over millions of years, it has learned to recognize a host of intruders, and so it has developed walls that keep out viruses, bacteria, chemicals and pollutants. Those walls also recognize elements that are vital to the brain, and give special permission to pass through the gauntlet of defenses. Your brain, though, isn’t expecting Stephanie Lopina.
The body, says Lopina, is well set up to deal with things it doesn’t want to see. Lopina is an assistant professor in the departments of chemical engineering and biomedical engineering at the University of Akron, and she is determined to use polymer science, biology and pharmacology to engineer a disguise so she can sneak past the body’s blood-brain barrier.
Lopina has pondered this barrier since 1990, when she started her doctoral studies at the Massachusetts Institute of Technology. At MIT, she studied the use of polymers as biomaterials in artificial organs, and by the time she joined the Akron faculty in 1997, she wanted to try her hand at producing polymer nanoparticles that could fool the brain. Her microscopic creation, if she is successful later this spring, will be a drug delivery vehicle that could revolutionize the way individuals with manic-depressive disorder are treated. She’ll have done this not by discovering anything new, but by piecing together techniques from a variety of scientific disciplines.
In an institutional-like office – cinder block walls, threadbare carpet and dim brown doors – that looks across to the gleaming building that houses the university’s nationally recognized department of polymer sciences, Lopina clinicly states her goal. “I’m going to use biology against itself.”
She won’t be the first to create a polymeric drug delivery scheme. Scientists have been doing this for about 25 years, and have developed therapies to deliver chemotherapy drugs, birth control medications and nicotine, among other drugs. Lopina, though, is breaking ground by going small, delivering drugs molecule by molecule in a controlled and non-invasive method. And she’s the first to target a mental illness with this new technology, as well.
Pharmaceutical drugs are a fact of life these days, and a topic of public discourse. As common as they are, though, drugs are far from perfect. To be effective, they must often be taken in high doses, or at frequent intervals. But this effectiveness involves flooding the body with chemicals—in the hope that some of the dose will get to the correct part of the body to treat the illness. The pills may have harsh side affects, and can be quite expensive. The ideal, says Lopina, would be to give the right concentration of a drug at the right time and in the right place.
So how to reach that ideal?
“I’m an experimentalist at heart,” she says. “All my degrees are in chemical engineering, and I approach things from that mindset, grabbing all the tools I need to accomplish a task.” From biology, she knows that blood vessels throughout the body are lined with loosely strung cells, which is how drugs can seep from the blood into the body’s organs. In the brain, though, blood vessels are nearly impenetrable. There, endothelial cells are lined end-to-end, with tight junctions – the cells are “glued together,” says Lopina. Enough drug molecules eventually do worm their way through these junctions to make current drug therapies work, though sometimes at great pains and costs.
“One thing I could do is punch holes through the barrier,” Lopina explains. “But then everything can get through.” Her solution is to send a drug through the cell instead of around it. But the drug needs to be hidden from the body’s defense mechanisms, and somehow Lopina must tag the drug so that it meets up with the targeted spot in the brain.
Lopina hadn’t decided on which drug to send, so she asked her students for suggestions. One of her undergraduates, a woman who suffers from bipolar disorder, gave a valuable first-hand account: The medication is potent, but has harsh side effects, making it a struggle to stay on the drugs. Lopina asked for more information, and the student scoured the available literature before presenting an in-depth study of the potential for targeted delivery of the anti-depressant drug Venlafaxine. Venlafaxine allows the brain to regulate the levels of seratonin and dopamine, hormones that control a person’s emotions.
With her strong commitment to involving her students in her research, Lopina gathered a team of 19 students, both undergraduate and graduate, to assist in this project. The National Science Foundation liked the idea of undergraduates working on groundbreaking research so much that it is backing Lopina with a four-year, $200,000 grant.
Lopina calls her students the “star group,” because the delivery vehicle they’re using is a star-like configuration of a polymer called poly (ethylene oxide). PEO is a common substance, found on the glide strips on men’s razor blades. Like most polymers, PEO is a string of repeated chemicals – in this case, CH2. The research group will bunch together hundreds of strands of PEO, and attach individual molecules of Venlafaxine in between each of the PEO strands. At the end of each PEO strand, Lopina will attach a ligand – an antibody that will seek out a corresponding homing device on the endothelial cells. When it’s completed, the polymer will look like a kush ball, says Lopina, referring to those kinetic balls of rubber threads.
Once ingested in pill form, that kush ball will find its way to the brain, where endothelial cells with the right receptors will recognize the antibody, absorb the polymer and then spit it out on the other side. Like a Trojan horse, the polymer can then release its drug in the brain, where “each molecule is its own stealth bomber,” says Lopina.
“I’m not inventing the drug, I’m making it more palatable,” she says. A more palatable drug means higher patient compliance, and better results. “My objective is to improve the quality of life by applying polymers in medicine.”
Her vision is already inspiring the next generation of biomedical engineers.
Undergraduate Michael Rottmayer came to Lopina two years ago, searching for something to spark his interest. An Akron native, Rottmayer had chosen the University of Akron because of the school’s highly respected engineering program and its world-famous polymer division. He wanted to specialize in biotechnology.
“Dr. Lopina sat down with me and gave me a brief overview of her current research,” he says. “The synthesis of star PEO polymers for drug delivery applications just stuck out. It fascinates me that, if you attach a targeting ligand to the polymer, it can seek out a particular site in the body, and once it is at the site, it can release the drug and then biodegrade.” Rottmayer is part of Lopina’s star group, and is paid by the NSF grant to assist on the project.
This research, says Rottmayer, is innovative in its promise to revolutionize the pharmaceutical industry. “Imagine being able to swallow a pill and have the entire drug get released in the part of the body that needs it. It doesn’t have to cycle throughout your body and cause unwanted side effects. The drug will be able to do its job at the specific site in a greater concentration and over a longer period of time.”
The synthesis of the star polymers can be tedious at times, says Rottmayer, but the team believes they’ve got a perfect candidate in the PEO polymer, because PEO is biodegradable and water-soluble – the human body is about 80 percent water – and it can float through the body unharmed, without itself doing the body any harm.
But this is just an idea, admits Lopina, and the polymeric delivery might not work as she hopes it will. By the beginning of summer, her team will know. She keeps busy with other interdisciplinary projects. She’s involved in research with Akron General Hospital to use polymers in the healing of wounds; with Akron City Hospital to deliver drugs to arteries after bypass surgery; and with the Northeast Ohio Universities College of Medicine to use polymers as scaffolding in the growing of organ tissue. And she will speak on biocompatibility – how the body reacts to new materials – at the exciting Human Genome Odyssey Conference to be held April 5-7 at the University of Akron.
Her message may not be groundbreaking, but her results just may be. “I didn’t discover anything,” says Lopina. “I’m just exploiting what has been discovered.” Progress, she’s finding, is sometimes a matter of simply rearranging the existing building blocks.
Anton Zuiker ☄
© 2000 Zuiker Chronicles Publishing, LLC