Breaking Down the Barrier

Padowski looks at ways to deliver drugs across the blood-brain barrier

Jeannie Padowski has received numerous awards and honors, including a Burroughs Wellcome Graduate Student Scholar Award and an Eli Lilly & Co.-UNC Predoctoral Fellowship in Pharmacokinetics, Pharmacodynamics and Drug Disposition.

As an undergraduate student studying brain and cognitive sciences at the University of Rochester, Jeannie Padowski became fascinated with the relationship between brain biochemistry and function.

Now a graduate student conducting research in the School of Pharmacy, she is turning her fascination with the brain into research that she hopes will help clinicians better understand and treat brain tumors. Padowski’s adviser is Gary M. Pollack, PhD, professor in the Division of Pharmacotherapy and Experimental Therapeutics and executive associate dean.

Padowski says that her interest in understanding human cognition and behavior led her to investigate the biological basis of brain function and eventually to focus on issues related to the toxic and therapeutic actions of chemicals in the brain. A summer research fellowship in pediatric oncology compelled her to concentrate her research efforts on brain tumors.

“Brain tumors generally carry a very poor prognosis, and in particular, they’re not well treated pharmacologically,” says Padowski, who is enrolled in UNC’s Curriculum in Toxicology. “One fundamental problem with pharmacotherapy for brain tumors—and most neurological diseases—is the inability to effectively deliver drugs across the blood-brain barrier into the brain.”

The blood-brain barrier is a structural and functional interface between the central nervous system and circulating blood that has evolved to keep toxic chemicals out of the brain. While a number of chemotherapeutic drugs have proven useful in fighting other cancers throughout the body, they have been of little help in treating brain tumors because the barrier keeps them from reaching the central nervous system. In addition, some drugs that would otherwise be able to penetrate the blood-brain barrier are pushed back into the bloodstream by a drug-effluxing transporter system called P-glycoprotein.

Padowski’s research is dedicated to achieving a better understanding of this process and to identifying practical approaches for delivering therapeutic agents to the brain to treat tumors. Her dissertation project incorporates a variety of strategies, including in vitro, in vivo, and mathematical modeling experiments.

The first stage of her research, which was conducted in vitro, involved applying paclitaxel, a common cancer drug, directly to brain tumor cells. Padowski says that before searching for ways to get the drug into the brain, she wanted to better understand how tumors respond to paclitaxel. Because researchers already know how paclitaxel works, she directed her studies toward understanding the time course of cellular response to the drug. Her examination, which focused on how the kinetics of drug exposure affected the dynamics of cell response, included variables such as drug concentration, frequency of administration, and duration of exposure of cells to the drug. She then developed a series of mathematical models based on her in vitro experiments that describe the relationship between drug exposure and cellular response.

“Once you develop a mathematical framework for understanding how the kinetics of drug exposure influence cellular response in a simple system,” she says, “you can use that model to help predict whether these tumor cells will be likely to respond to a therapeutic regimen that produces a given pattern of drug exposure in an intact brain.”

Padowski’s in vivo research involves using paclitaxel together with a chemical inhibitor of P-glycoprotein in an animal model, and measuring the brain concentrations of paclitaxel that result from different combinations of the two compounds. The inhibitor alters the normal function of P-glycoprotein, allowing paclitaxel to pass the blood-brain barrier more easily. She says she will determine how to best co-administer the two compounds to allow them to work optimally. She then hopes to develop models describing how brain exposure changes with different combinations of paclitaxel and P-glycoprotein inhibitors. Ultimately, she wants to integrate the models from her in vitro and in vivo studies to provide a more complete picture of the relationship between drug administration and cell response.

“One attractive aspect of this project is that it’s not limited to one type of research method; it uses a range of experimental tools to try to understand how the blood-brain barrier limits drug penetration into the brain,” Padowski says. “And although it is focused on brain tumor therapy, this research is relatively basic in nature, and it has the potential to inform the study of pharmacological treatments for many types of neurological disease.

“My intent is that this project will improve understanding of certain processes by which the blood-brain barrier limits the uptake of drugs into the brain. As researchers develop new compounds to treat neurological diseases, it’s increasingly important to know how to enable these compounds to penetrate into the brain. I would hope that this research can help direct future efforts toward brain targeting of neurotherapeutics.”