UVA engineers develop drug carrier-like

A drug molecule designed to bypass the lungs' natural defenses and thereby cure disease offers new hope to people with chronic or fatal respiratory diseases, say its developers, researchers in Assistant Professor Liheng Cai's Soft Biomatter Lab in the University of Virginia's School of Engineering and Applied Science.

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

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

Leaving our defense behind

Our lungs have protective layers that trap pathogens or inhaled particles and transport them out of the respiratory tract to prevent us from becoming sick.

Every time you blow your nose, the system works.

“Unfortunately, these same barriers also prevent drugs from reaching 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 airways by mimicking mucins, a natural glycoprotein responsible for the properties of mucus and has the same bottlebrush shape – a central spine with a thicket of bristles pointing outward.

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

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

To test their hypothesis, the team cultured 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 mucosa and the periciliary layers – the latter being the gel that coats the cilia. They did not stain the epithelial cell walls, which helped mark the boundaries of the epithelium.

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

A series of recent successes

“The microhuman airway is essentially an equivalent site for cell growth,” Huang said.

“Because of the biological similarities, we can study the defenses of the human lung without harming living beings,” added Cai, whose lab specializes in developing novel bottlebrush polymers for a range of applications, many of which push the boundaries of precision medicine.

For example, his bioprinting program recently produced what may be the first 3D building block for on-demand organ printing. He also just won the prestigious $1.9 million Maximizing Investigator's Research Award from the National Institutes of Health, one of several awards for emerging scientists in his career.

The PEG-BB results are another success for the laboratory.

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

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

publication

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

This work was supported by 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.