Cai and his team, including materials science and engineering student Baiqiang Huang and biomedical engineering student Zhi-Jian He, successfully demonstrated the effectiveness of the nanocarrier using the lab’s own “micro-human airways.” The device captures the geometric and biological characteristics of human airways.

They described their findings in a paper published June 27 in the Journal of the American Chemical Society. ACS Nano.

Sneaking past our defenses

Our lungs are equipped with protective layers that capture pathogens or inhaled particles and transport them out of the airways, so that we do not become ill.

Every time you blow your nose, the system works.

“Unfortunately, these same barriers also prevent drugs from reaching their target cells, making it difficult to treat diseases such as asthma, chronic obstructive pulmonary disease and pulmonary fibrosis,” Huang said.

The new polymer is called bottlebrush polyethylene glycol, or PEG-BB. It moves quickly through the airway walls by mimicking mucin, a natural glycoprotein responsible for the properties of mucus, which has the same bottlebrush shape — a central spine with a tangle of bristles extending outward.

“We thought the flexibility and worm-like geometry of the bottlebrush carrier would allow it to slip through the dense network of mucus and gel surrounding the cilia, where it would be taken up by epithelial cells, where the drugs would need to do their work,” Huang said.

Cilia are the hair-like structures on the surface of cells. They move together with mucus to repel and expel foreign bodies.

To test their hypothesis, the team grew human airway epithelial cells in their device. They introduced fluorescent PEG-BB molecules into the cells from two directions.

They then used a dye that can penetrate the mucus and periciliary layers, the latter being the gel that coats the cilia. They did not stain the epithelial cell walls, which helped to mark the boundaries of the epithelium.

Using a special microscope and a darkened room to sharpen the images, they could see how well the glowing bottlebrush molecules had passed through the cells.

A series of recent successes

“The micro-human airways are in principle an equivalent place for cells to grow,” Huang said.

“The biological similarities allow us to study the defenses of the human lungs without harming living beings,” adds Cai, whose lab specializes in developing novel bottlebrush polymers for a variety of applications, many of which push the boundaries of precision medicine.

For example, his bioprinting program recently produced what could be the first 3D building block for printing organs on demand. He also recently won a prestigious $1.9 million Maximizing Investigator’s Research Award from the National Institutes of Health, one of several recognitions of rising stars in his career.

The PEG-BB findings are a new success in the lab’s series.

“We believe this innovation not only promises better treatments for lung diseases with fewer side effects, but also opens up possibilities for treating conditions that affect mucous membranes throughout the body,” Cai said.

The lab’s next step is to test PEG-BB’s ability to transport drug molecules across a mucus barrier. The team is experimenting with both in vitro and in vivo models in mice.

Publication

Bottlebrush Polyethylene Glycol Nanocarriers Translocate Across the Human Airway Epithelium via Molecular Architecture-Enhanced Endocytosis was published on June 27, 2024 in ACS Nano.

This work received funding from the National Science Foundation, UVA LaunchPad for Diabetes, UVA Coulter Center for Translational Research, Juvenile Diabetes Research Foundation, Virginia’s Commonwealth Health Research Board, and the UVA Center for Advanced Biomanufacturing.