Chemistry students build ‘smart’ drugs

A team of Pitt undergraduates could soon find a new way to fight cancer and simultaneously…

Zach Schaffer, Staff Photographer

Akira Shimizu, senior chemistry and physics double major, works with other undergraduates on the 14th floor of Cheveron Hall to synthesize more flexible drug delivery molecules.

A team of Pitt undergraduates could soon find a new way to fight cancer and simultaneously control the harmful effects of nuclear fallout.

Under the guidance of Paul Floreancig, a professor in the Department of Chemistry, three Pitt seniors majoring in chemistry are building a microscopic drug-delivery system that could have wide-ranging applications for human health.

“What they are doing is trying to make smart drugs,” Floreancig said.

Second-year natural sciences students commonly dread organic chemistry exams, but nothing wets the palms more than one kind of test question: organic synthesis. Having to propose step-by-step roadmaps from simple starting materials to complex molecules, students must carefully mix creativity with academic mastery, and such demands can overwhelm many.

But not Akira Shimizu, Stephanie Garrell and Suzanne Principe, who day after day in Floreancig’s laboratory follow much the same process of molecular engineering. The difference is that in their case, no teacher can tell them the right answer.

“A lot of times with organic research, you’re working with molecules that no one worked with before,” said Shimizu, who started contributing to this project for his summer Brackenridge Fellowship, an interdisciplinary research award for Pitt undergraduates funded by the University Honors College.

Armed with a panoply of chemicals and equipment, the student team is set on building molecules that have never existed. The proposed application is just as ambitious: to produce drugs that selectively affect their biological targets without touching other parts of the body.

“The end result is getting them into cells and seeing how they react toward their target,” said Garrell, who, along with Principe, joined the project this semester. Such insight could then translate into better ways to conduct chemotherapy and protect from nuclear radiation.

But testing the team’s molecular products in cell cultures, let alone animals or humans, is a long way off. They have to first make the products.

In the chemistry students’ case, the desired products are new kinds of “prodrugs.” Unlike traditional pharmaceuticals that enter the body in active form, a prodrug can only elicit its therapeutic effect after one or more biochemical processes convert the drug to its active form. Prodrugs have reached widespread clinical use, from treating high blood pressure to cancer: The idea for chemotherapy is for the drug to become toxic when it hits cancer cells, sparing normal cells.

Despite their preponderance, the problem with prodrugs is that their structures lack generalizability. That’s because, most often, researchers construct them with only the indicated purpose in mind, reinventing most of the wheel each time.

In contrast, Shimizu, Garrell and Principe want to fashion a common, customizable wheel.

“What we’re trying to do is make one where it is easy to change … what drug you’re delivering, to change what you’re targeting and change what sets it off,” Shimizu said.

In that end, the undergraduate team is busy synthesizing several templates of prodrugs, built of three molecular “groups” capable of customization. Leaning heavily on scientific literature for procedural clues, the students spend lab time assembling the groups through a series of sequential chemical reactions, purifying the intermediate products and confirming they got what they intended.

Once combined in multifunctional molecules, the “targeting” group would attach to the area of interest, the “triggering” group would convert the drug into active form, and the “cargo” group would deliver the payload — the substance that actually changes, protects or kills the target.

After basic preparations prove effective and viable — the group hopes to be ready for cellular testing by December — scientists elsewhere could modify the different “groups” to fit their respective therapeutic objectives.

“It’s a very generalized approach to delivering different molecules to different environments,” Floreancig said.

That could mean eliminating many kinds of cancer cells, but it could also mean safeguarding mitochondria, a critical cellular component affected by nuclear radiation. Experimental evidence suggests that mitochondria exposed to radiation increase production of reactive oxygen species, which are unstable particles that, in high amounts, tear cells apart. Thus, there’s a big push to find ways to deliver drugs that counteract these species to mitochondria in tissues especially vulnerable to radiation, like bone marrow.

Drugs like that could be quickly distributed to people after a nuclear emergency, according to Joel Greenberger, chair of the Department of Radiation Oncology and leader of the campus-wide grant from the National Institutes of Health that partially funds Floreancig’s work.

“The main aim of the grant is to develop small molecules to be used as radiation mitigators,” Greenberger said. “These would be drugs that can be given to people after radiation events to try to protect their bone marrow and their gastrointestinal systems. This would be for willful acts of terrorism.”

Resisting terrorism with molecular engineering takes time and focus. Shimizu, Garrell and Principe each plan to invest hundreds of hours on the 14th floor of Chevron Hall by the semester’s end.

“I’m always thinking about when I can get homework done so that if my work in the lab runs a little bit longer than expected, I’ll still be OK,” Garrell said.

Careful thinking might be critical to conducting research, but involvement in research has also affected the ways team members think.

The familiar experience of chemical reactions producing unexpected results has helped Principe, who intends to someday work in chemical industry, put failure into perspective.

“Not everything’s going to work, but you can always try it again and try it a different way,” she said. “And hopefully it will work.”

Shimizu, who is applying to graduate schools for chemistry, echoes that perspective, going as far as invoking chaos theory, which states that many phenomena are unpredictably governed by tiny changes in often-unknown conditions.

“One of the good things about having to do research is being able to roll with the punches,” he said. “Sometimes reactions don’t work because maybe it was a bad day to run that reaction.”

But for every ounce of insight, the students extract the same in personal reward.

For Principe, her time in research has been empowering.

“I feel a lot more confident in my abilities as a chemist after working in Dr. Floreancig’s lab,” she said in an email.

The satisfaction of novel creation drives Shimizu, who spent his childhood playing with Legos.

“I really enjoy synthetic organic chemistry, in that you’re building chemicals from the ground up,” he said.

And for Garrell, who’s open to any way to involve science in her future, the thought of her team’s drug delivery system improving human health is invigorating.

“What we do, we hope has biological applications to eventually help someone,” she said.