Manipulating charges on molecules facilitates transport, MIT Post-Doc Leon Li demonstrates
The mucus barrier prevents passage of harmful germs wherever it covers delicate wet cells in the human body called epithelia, but it also poses a major obstacle for the delivery of drugs. One important question in the field is how to equip drug delivery vehicles so they manage to pass through the protective mucus barrier.
|Dr. Leon Li holds a microfluidic device used to test how effectively molecules called peptides can pass through a mucus barrier. Photo: Denis Paiste, Materials Processing Center|
Recent research by MIT postdoctoral associate Dr. Leon Li shows that ionic charges on molecules and the spatial arrangement of those charges each play a key role in transport through mucus.
Li created a microfluidic device that creates a tiny mucus barrier, mimicking the body's own. "Our microfluidic devices are designed to study animal and human mucus samples and experimentally mimic the geometry and physiology of the body's natural mucus barriers. We use these devices to perform detailed measurements of the interaction of molecules, viruses, and drug carriers with the mucus barriers. We also used these devices to study acid transport through mucus barriers. I realized that could be used to study protein transport and drug transport, so I adapted those devices," Li said. The Laboratory for Biological Hydrogels now has a suite of microfluidic tools designed and fabricated by Li in collaboration with Prof. Jongyoon Han's lab. The devices allow the researchers to reconstitute specific aspects of mucus transport that are much easier to measure outside the body.
To probe the fundamental criteria underlying the selective filtration properties of the mucus barriers, Li used microfluidics in conjunction with novel peptide based molecular probes.
Close up image of microfluidic device with U.S. quarter for comparison.Li used fluorescent microscopy, a well-established technique, to image and compare the differences in mucus penetration by differently configured peptides.
Four groups of peptides were tested: positively charged peptides, negatively charged peptides and peptides carrying a mix of negative and positive charges in two different arrangements.
"The mucus interacts with the peptides to change the transport of these peptides in very specific ways depending on what peptide it is and how the charge is distributed on that peptide," he said. By using isomers of a peptide – peptides consisting of the same number of atoms but with different spatial arrangements of their atoms and charges – Li and colleagues were able to show in the "Biophysical Journal" paper, "Spatial Configuration and Composition of Charge Modulates Transport into a Mucin Hydrogel Barrier," that spatial arrangements of ionic charge can affect transport.
Nanometer scale changes
|DR. LEON LI|
These changes can take place on a very small scale, on the order of nanometers, Li said. The peptides he studied are about 10 nanometers long. "When you make arrangement changes on the order of nanometers, you can modulate the transport behavior of molecules inside of mucus," he said.
The new findings point to a new tool for designing drug and gene carriers – specific surface charge configurations to optimize interactions with mucins in mucus for diseases such as cystic fibrosis and gastric ulcers. The paper's authors included Ribbeck, EECS Professor Jongyoon Han, MIT post-doctoral associate Thomas Crouzier (link to Crouzier article), electrical engineering graduate student Aniruddh Sarkar and biological engineering graduate student Laura Dunphy.
Drugs carriers have either been positively, negatively or neutrally charged and thought of as either adhesive or non-interactive. But Li's research opens a new set of possibilities based on nature itself to use spatial configuration on a very small scale as a selectivity criteria for transport across mucus barriers. "We are showing, in a sense, an additional finely tuned lever that lets us optimize how we send drugs across mucus barriers," Li said. The research also opens the possibility of engineering different materials or molecules that can improve mucus barrier function.
Strengthening the mucus barrier against chemical and biological agents might also be used for defense applications. The work did not consider hydrophobicity, which opens another line of inquiry for future work.
"Our contribution here is demonstrating that our very precise tools using peptides with very precise variations on charge – spatial variation of charge – can have profound effect on transport into mucus barriers." Li said.
Li, who enjoys hiking, cooking and socializing, hopes to work as research scientist or engineer in industry when he finishes his work as a post-doc at MIT.