Exploring A More Convenient Chemotherapy
What if, instead of spending hours several days a week at the hospital undergoing chemotherapy treatment, a cancer patient could take a pill in the comfort of his or her own home? Graduate Program in Bioengineering student and alumna Deborah Sweet Goldberg (B.S. '06, chemical engineering) hopes her research will one day answer that question. Her proposal, "Anionic PAMAM Dendrimers for Oral Delivery of 5-Fluorouracil," which described the development of an oral delivery system for chemotherapy drugs that are traditionally administered intravenously, earned her the 2009 Fischell Fellowship in Biomedical Engineering.
During her time at the Clark School, Goldberg was co-advised by Graduate Program in Bioengineering adjunct faculty members Professor Hamid Ghandehari (Department of Bioengineering, University of Utah) and Professor Peter Swaan (Department of Pharmaceutical Sciences and Center for Nanomedicine & Cellular Delivery University of Maryland School of Pharmacy). She conducted most of her research in Swaan's laboratory on the University of Maryland‚ Baltimore campus.
Goldberg's chemical and biomolecular engineering background prepared her to pursue her interest in creating more effective cancer treatments as a graduate student. "As an undergraduate I was always leaning toward the more biochemical end of the spectrum," she says. "One of the most fascinating things I learned about was the field of targeted drug delivery, which uses different synthetic strategies to create 'smart drugs' that can be guided to a specific site."
Typically, an ingested or intravenous drug travels all over the body and treats what it encounters, whether it needs to be treated or not. "One of the big problems with cancer drugs now is that they're really good at killing cancer cells, but unfortunately they're also really good at killing the other cells in your body too," Goldberg explains. "They affect the immune system and bone marrow, so doctors have to limit treatment to only as much as the patient can tolerate without getting even worse. Targeted drug delivery tries to solve these problems."
Oral drug delivery, she says, can be very challenging. An oral chemotherapy drug would not only have to survive the harsh environments in the stomach and intestines, but also be able to pass through the intestinal wall, find its target, and treat a tumor as effectively as an intravenously-delivered drug could. Many chemotherapy drugs, including 5-Fluorouracil (5-FU), which Goldberg uses in her work, are incapable of overcoming these obstacles on their own, which is why they must be delivered intravenously.
Goldberg's strategy was to use dendrimers‚ nano-sized, highly branched synthesized polymers with defined, controllable structures‚ as carriers for 5-FU. Dendrimers are capable of crossing biological barriers in the digestive tract and heading out into the rest of the body, taking their chemotherapy cargo with them.
The commercially available dendrimers she used, called poly(amidoamine)s, have a roughly spherical "starburst" configuration that looks something like the branches of a tree growing out symmetrically from a center point. Each branch splits into more‚ four becoming eight, eight becoming sixteen, sixteen becoming thirty-two‚ resulting a group of sixty-four twigs on the outside of the sphere. These "twigs" are called terminal groups, and it is to them that Goldberg can attached not only 5-FU, but also targeting and imaging molecules that can help guide the dendrimer to a tumor site and allow doctors to track its progress visually using a technology such as magnetic resonance imaging (MRI).
Goldberg modified the 5-FU molecules by attaching a dipeptide, a small molecule made of two amino acids, to them. With its chemotherapy molecule in tow, the other end of the dipeptide, referred to as a "linker", was then coupled (attached) to one of the dendrimer's terminal groups.
That's when things got tricky. "You can't just load up the dendrimer with 5-FU and send it off into the body," says Goldberg. "With every molecule you add, you're changing the physical properties of the dendrimer, so it might act differently than you'd expect. I found, for example, that the surface charge of the dendrimer is very important, so if I put a 5-FU molecule on all sixty-four of its terminal groups, I'm going to lose all of my surface charge, and it's not going to be able to pass through the intestinal barrier."
In order to make a dendrimer into the most effective carrier possible, Goldberg had to discover the best drug conjugation ratio (the number of 5-FU molecules attached to each dendrimer), and select the best dipeptide linker for the job. There had to be enough 5-FU molecules to treat the cancer, but not so many that the dendrimer couldn't get to the tumor site. The linkers needed to be strong enough to hang on to the 5-FU for most of the trip, but be able to release the drug when the time was right.
After a series of dendrimer/5-FU/linker combinations are produced, they were put through two tests using cell-based models: one for toxicity, which determined if the package can get the drug to the cancerous cells before any harm is done to healthy ones; and the other for transport, to determine how easily it can pass through the intestinal barrier. There are so many possible combinations that a major research effort was–and still is–required to find one that could be as effective in treatment as intravenous drug delivery.
Goldberg's work was only the beginning of a long journey toward an effective oral chemotherapy solution. "Through the Fischell Fellowship competition, I learned so much about the FDA approval process and everything you need to get a drug from the lab to commercialization. It could take hundreds of millions of dollars to get a drug from conception to market. That's why big companies like Merck and the Pfizer are the ones producing new drugs: You have to have drugs on the market to generate the funding for the new ones."
While a single bioengineer may not be able to introduce a new drug on her own, Goldberg's work was no less important because it created a knowledge base that might ultimately end up in a pharmaceutical company's toolbox. Her experiences in the Fischell Fellowship competition, her research, and an internship at MedImmune prepared her for her ultimate goal: conducting pharmaceutical or biotech research and development in industry.
Goldberg originally chose to attend the University of Maryland as an undergraduate because it combined a strong engineering program with a balanced overall educational experience. She also discovered Maryland's welcoming attitude. "I felt that Maryland found a lot of ways to make a small school out of a big school. I never, ever felt like a number. I had such good interactions with my professors, and [the A. James Clark School of] Engineering really creates a community feeling."
She decided to stay for the "newness" of the Fischell Department of Bioengineering and flexibility of the graduate program. "I think Maryland really is on the cutting edge of things," she says. "We have a lot of young, energetic professors who are doing the latest, greatest things in bioengineering. If you look at the graduate program [faculty list], there are over 50 professors you could work with, so you can really find your niche. I know a lot of people who do their research at the NIH and the FDA, with the School of Pharmacy, the School of Medicine‚ I love that the program has these relationships. It's a huge advantage."
She also appreciates her fellow students: "I had a very tight [cohort] group my first year. We would always study together." Even when she was working on the UMB campus, she kept in touch.
Goldberg believes pursuing a graduate degree in bioengineering is a great option for students who really enjoy research and who want to specialize, whether for academia or industry. "If you want to be able to guide your own research I think graduate school gives you the opportunity to focus on something that's really important to you and then make it your career."