A drug-carrying molecule designed to cure disease by slipping past the lungs’ natural defenses offers new hope for people with chronic or fatal respiratory conditions, say its creators, researchers in Assistant Professor Liheng Cai’s Soft Biomatter Lab the University of Virginia School of Engineering and Applied Science.
Cai and his team, including materials science and engineering Ph.D. student Baiqiang Huang and biomedical engineering Ph.D. student Zhi-Jian He successfully demonstrated the effectiveness of the nanocarrier using the laboratory’s own ‘micro-human airway’. The device captures the geometric and biological characteristics of human airways.
They described their findings in a paper published June 27 in the journal American Chemical Society ACS Nano.
Sneak past our defenses
Our lungs have protective layers that capture and transport pathogens or inhaled particles from the respiratory tract to prevent us from getting sick.
The system works every time you blow your nose.
“Unfortunately, those same barriers also prevent drugs from reaching targeted cells, making it difficult to treat diseases such as asthma, chronic obstructive pulmonary disease and pulmonary fibrosis,” Huang said.
The new polymer is called bottle brush polyethylene glycol, or PEG-BB. It moves quickly through the airways by mimicking mucins, a natural glycoprotein responsible for the properties of mucus, which has the same bottlebrush shape: a central spine with a thicket of bristles extending outward.
“We thought the bottlebrush carrier’s flexibility and worm-like geometry would let it sneak through the dense network of mucus and gels surrounding the cilia to be internalized by epithelial cells, where the drugs are needed to 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 engulfs the cilia. They did not stain the epithelial cell walls, which helped mark the boundaries of the epithelium.
Using a specialized 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 micro-human airways are basically an equivalent home for the cells to grow,” Huang said.
“The biological similarities allow us to study human lung defense, without harming living things,” added Cai, whose laboratory specializes in developing new bottle brush polymers for a range of applications, many of which are pushing boundaries in the field of precision medicine.
For example, its bioprinting program recently produced what could be the first 3D building block for on-demand organ printing. He also just won a prestigious $1.9 million Maximizing Investigator’s Research Award from the National Institutes of Health, one of several rising stars in his career.
The PEG-BB findings represent a new set of successes from the laboratory.
“We believe this innovation not only promises better treatments for lung diseases with fewer side effects, but also opens up opportunities for treating conditions that affect mucosal surfaces 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 experiments 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 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.
