When designing viable drugs or drug delivery methods, control over materials is key. It’s also a challenge, one that Christopher A. Alabi, Chemical and Biomolecular Engineering, pursued when he began building a new type of polymer at Cornell University.
“I wanted to use polymers to design drugs and deliver drugs, but I didn’t want to use off-the-shelf polymers,” Alabi says. The problem with existing polymer production, Alabi explains, is that the standard methods yield batches of polymers with varied molecular weights, like a pot of cooked spaghetti with strands of different lengths.
“We wanted to make our own new polymers that were mono-disperse, with a single molecular weight and a defined sequence,” Alabi continues, “because if you have control over size and sequence, you can start to understand and control conformation. You can then perhaps control how that polymer folds and arranges itself in space and how it interacts with the biological system.”
Alabi and his team designed a new process and a new class of short polymers, called oligothioetheramides (oligoTEAs). In a number of projects and applications, the polymers are demonstrating their potential to fight human disease.
OligoTEAs, Weapons for Defeating Pathogens
The oligoTEAs, short polymers composed of only a few units, can be programmed to exhibit certain chemical and physical properties. They can therefore be designed as weapons to target pathogens.
Bacterial cells are relatively good targets, because their surface properties don’t resemble those of human cells. “Bacterial cells tend to be more negatively charged and have certain lipids in them, certain molecules on their cell membranes that your normal cells don’t have,” Alabi says. “We can then take the complementary property and design that into oligomers so that they can find and select the harmful bacterial cells without engaging normal eukaryotic cells.”
Once the oligomers find the bacteria, they still have to fight it. OligoTEAs, however, can be made lethal. “We can tune the properties of these oligomers such that when they bind to the bacterial cells, they compromise the cell membrane and essentially kill it,” Alabi says. “They permeabilize the cell membrane, and the bacteria spits its guts out.”
Alabi and his team have promising preliminary data, with particular success fighting Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE). They are currently working with collaborators at the National Institute of Allergy and Infectious Diseases to transition to more deadly pathogens and then animal studies. As this research progresses towards application, Alabi has an even more difficult target in his sights.
Novel Strategy for Chemotherapeutics
“Cancer cells are more difficult because they’re just like regular cells,” Alabi says. “There is no magic bullet. They don’t have some weird protein that’s not present everywhere. Cancer is just your normal cells going haywire.”
This makes cancer cells much harder to target for drug delivery. “The chemotherapeutic has limited selectivity. It goes all over your body,” Alabi says, “which is why patients receiving chemotherapy develop severe side effects.”
New strategies, however, can link the chemotherapeutic to a protein that goes specifically to a type of cell in your body. “So the drug is now dragged by this protein only to your target cell,” Alabi explains.
In order for the therapeutic to do its job, it still needs to enter the cell and detach from the protein. That’s where Alabi’s oligoTEAs come in. “We’re making oligoTEA-based linkers that are degradable on cue and only degradable in a certain target cell,” Alabi says.
It’s not easy because the enzyme to which the oligoTEA linker responds can be found in normal cells as well as cancer cells. “The main difference between a cancer cell and a normal cell is that they over-express or under-express certain proteins,” Alabi explains. “So you have to engineer the linker’s kinetic properties—how fast it cleaves—so that it responds better to your cancer cells because cancer cells may have more of that protein or enzyme. That’s how you drive the selectivity.”
Now, Alabi and his students are working to engineer that function in the linkers. “We want to tune the kinetics of cleavage such that it is much more responsive to cancer cells than normal cells,” he says.
“We can tune the properties of these oligomers such that when they bind to the bacterial cells, they compromise the cell membrane and essentially kill it.”
Technology and Basic Research Combined for a New Expertise
Alabi has always loved chemistry, with an early interest in how all types of molecules form. At the same time, Alabi didn’t “want to do chemistry for chemistry’s sake,” he says. “I wanted to make molecules that did something. I wanted that application part of it, so I was pulled to engineering from the get-go.”
Sometimes the potential application requires fundamental research, however, and Alabi’s team has projects underway to fully understand the behavior and potential of what they’ve created. “What do these oligomers look like in solution? Are they floppy, do they dance around a lot or a little?” Alabi says. “What’s their flexibility in solution? How can we develop new techniques to understand their structure?”
Pursuing answers to these questions has led to new approaches. “We’re combining known techniques in different ways, trying to extract more information out of them,” Alabi says. “By combining a couple of data points from existing techniques, and using a bunch of really cool chemical and engineering mathematics, you can essentially model the polymer and figure out what the shape is and how it conforms in solution.”
Comfortable with Variability
Alabi’s little secret is that he never took a biology class during his undergraduate studies. “It still shocks me that I didn’t have to,” he laughs.
When Alabi went to graduate school at California Institute of Technology, he joined the side of Mark E. Davis’ chemical engineering lab that focused on making membranes for fuel cells. He had no contact with the biology side of Davis’ lab. “We coexisted but were completely separate,” Alabi says.
Davis began asking Alabi to make molecules for the biology side, where they were developing nanoparticles for therapeutic RNA delivery. “Mark asked me to make him this molecule, so I did, and then he asked for another one, and he kept asking, and I kept making them, and then he finally said, ‘Maybe you should come to our bio group meetings.’”
Alabi was the first to straddle both sides of the lab, and it whetted his appetite for the discipline, despite the challenges of biological problems. “You have to get really comfortable with variability and not being able to fully control your system,” he says.
This comfort with variability has been good for another aspect of Alabi’s life—his teaching. “Recently, what I find most satisfying are the students and their metamorphoses and the challenge of figuring out what motivates one student versus another.
“I’m watching as they slowly go from my students to my peers. I can see that right before my eyes,” Alabi continues. “I think when you start out, you want your students to be just like you. Now, I want them to be different and their own because that brings new ideas and different ways of doing things.”