Create mobile models to study how drugs move around the body


The human body has built-in protections to prevent pathogens from entering.

That sneeze or that stuffy nose when you have a cold? Your body uses the mucous membranes of your respiratory system to expel the offending virus.

But these natural defenses also sometimes work to keep drugs out, a difficult problem that has hampered treatment solutions for diseases such as cancer, fibrosis and even COVID-19.

Catherine Fromen, a chemical engineer at the University of Delaware, wants to better understand how these organ protection mechanisms work to improve the delivery of therapeutic drugs to the body.

Fromen received a $ 2 million grant from the National Institutes of Health (NIH) Maximizing Investigator’s Research Award, which provides promising early-career researchers with sustained funding to pursue new ideas.

The five-year MIRA grant will support Fromen’s main areas of work focused on the design of drugs that go to mucosal interfaces, such as inhalable vaccines for respiratory problems. She is particularly interested in where these drugs need to go to overcome mucosal barriers, for example in the lungs or gastrointestinal tract, to better interact with immune cells.

“By better understanding how mucus and cells behave at these mucous barriers, we can better design methods and drugs to treat different problems at these protective barriers,” said Fromen, assistant professor in the engineering department. chemical and biomolecular.

UDaily caught up with Fromen to find out more about his plans to move this work forward.

Q: What are mucosal interfaces and why are they so important to human health?

Fromen: Mucosal interfaces are found in the respiratory, gastrointestinal, reproductive and urinary systems of the human body. These are the sites where we are most vulnerable and where pathogens infect first. Single immune cells can act independently of the body’s overall immune system to produce region-specific responses to any foreign invaders. If we can deliver drugs directly to these cells on the front line, then we can think about improving the protective barrier and fighting off pathogens. With the lung, it could be solutions for diseases like lung cancer or infectious diseases like COVID-19 or the flu. In the gut, it could be celiac disease, which is an inappropriate immune (autoimmune) response to gluten in certain foods.

Q: How do mucosal barriers work and how do we want them to work better?

Fromen: The body’s immune system is often thought of as an army, where each of the different types of cells has different military functions. You can think of the mucous interface as the walls of a castle, with infantry cells patrolling the castle and watch cells looking for trouble on the horizon. Either of these cells can enter the castle and say, “Go up; it’s time ”and guide the body’s response to different problems.

These immune cells spend a lot of time on this protective layer, waiting for the right signal to do something. If we can flip a switch here, it can create a whole cascade of events to do something totally different that benefits the whole organ or the patient.

Q: Can you share an example?

Fromen: Sometimes these cells have been poorly trained to be overprotective in a way that has unexpected side effects. Maybe the cells in this mucous interface are supporting a tumor cell and they shouldn’t be – can we give instructions to alert immune cells that the tumor cell is bad, so they wake up and do everything they’re normally good at?

Currently, we can only provide one-word instructions so that these cells can mobilize the troops to perform complicated actions. We need to be able to send better and more frequent messages to these cells.

Q: Where will you start?

Fromen: We will first focus on the lung because it is an area of ​​expertise for my laboratory. However, the work is more broadly applicable to mucosal interfaces in other places like the human intestine, as both organs are in constant motion and have a huge surface area.

In previous work, my lab created a 3D printed lung model that incorporates the unique branching architecture of the tissue. We plan to add movement to our model and run fluids and drugs through it to understand how the system works at a fundamental level. Researchers have studied on a small scale how mucus flows from left to right or how things diffuse through it, but no one has looked at the more important transport mechanisms – how thick the mucus is, how long things take can stay in one place, how things change. . We want to see the lung move when it creates air and mucus on it, to study how drugs move through this macroscopic frame, before they even get to the mucus.

Q: What will this tell you?

Fromen: One of the biggest challenges we face from a pharmaceutical perspective is not knowing where the drug goes once inside the body. We can build simulation models to explore things like how drugs diffuse through tissues when we place them in specific branches of the lung, but we don’t know how to predict, effectively, where it goes inside. of the whole organ or how long it will stay there. The same is true in the gut. We can estimate, but each body is different.

Additionally, most studies and simulations of how drugs move around the body assume a healthy person of a particular body weight. This can be problematic, as we know that a person’s lungs can look incredibly different depending on smoking status, age, or weight. At present, however, there is no way to incorporate this information into predicting the effect of drugs. This is where our model comes in.

Q: Why is it important to be able to study this movement?

Fromen: Even something as simple as opening or closing the epiglottis – that little flap in your throat that covers your esophagus when you swallow – is difficult. But it’s a real pinch point for inhaling drugs, so even a model with just a little movement could provide important information on how drugs move or disperse under various conditions, for example, breaths. short and shallow compared to longer, deeper breaths.

Q: What other issues do you plan to address?

Fromen: The other side of the job is focused on understanding what happens when the drug gets where it goes. We need to find out how the drug formulation design interacts with specific immune cells that live at the mucosal barrier level. We have interesting data that these cells can live longer by absorbing foreign objects (drugs, viruses) and that their lifespan at the mucosal interface is regulated by the frequency of these interactions.

These sentinel cells are essential for gathering outside information and coordinating the tissue response. We want to explore whether by changing the chemistry of the inhaled drug formulation we can turn knobs to control what these immune cells do, and for how long, to create the desired effect.

Q: Where do you hope this work will lead?

Fromen: There are so many diseases that originate from this mucous interface, so it is a real opportunity to improve human life. Think about vaccines… if we can better understand how to deliver drugs to treat cells directly to the site, it will be even better than getting a shot in the arm. I would love to see what we do become therapeutics that end up being approved by the FDA to help patients with respiratory problems in my lifetime, or see our models used to screen therapies and advance personalized medicine.

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