A newly developed drug-carrying molecule that outsmarts the lung’s defenses offers promising prospects for individuals grappling with chronic or severe respiratory conditions, according to its creators from assistant professor Liheng Cai’s Soft Biomatter Lab at the University of Virginia School of Engineering and Applied Science.
Cai and his team, which includes Ph.D. candidates Baiqiang Huang in materials science and engineering and Zhi-Jian He in biomedical engineering, successfully showed how effectively the nanocarrier works using the lab’s innovative “micro-human airway” model, which replicates the structure and biological functions of human airways.
Their results were detailed in a paper published on June 27 in the American Chemical Society journal ACS Nano.
Bypassing Our Protective Barriers
The lungs have multiple layers of defenses that catch and transport harmful pathogens or particles away from the respiratory tract to keep us healthy.
This mechanism operates every time you clear your nose.
“Regrettably, these same protective features also hinder medication from reaching intended target cells, complicating the treatment of conditions like asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis,” Huang noted.
The new polymer, known as bottlebrush polyethylene glycol, or PEG-BB, navigates the airway’s defenses by imitating mucins—natural glycoproteins that give mucus its characteristics; it features a bottlebrush structure with a central spine and numerous bristles extending outward.
“We hypothesized that the adaptable, wormlike design of the bottlebrush carrier would allow it to weave through the dense mesh of mucus and gels surrounding the cilia, ultimately being taken up by epithelial cells where the treatment is required,” Huang explained.
Cilia are tiny, hairlike projections on cell surfaces that work with mucus to push out unwanted particles.
To verify their theory, the researchers cultivated human airway epithelial cells in their device and introduced fluorescent PEG-BB molecules into the cells from two different angles.
They used a special dye capable of penetrating the mucus and the periciliary layer (the gel covering the cilia), while avoiding staining the epithelial cell membranes, which helped delineate the boundaries of the epithelium.
Employing a specialized microscope in a darkened environment to enhance image clarity, they observed how effectively the glowing bottlebrush molecules traversed the cells.
A Series of Recent Achievements
“The micro-human airway essentially provides a safe environment for cells to thrive,” Huang stated.
“Its biological resemblances allow us to examine human lung defenses without inflicting harm on living organisms,” Cai added, highlighting the lab’s focus on creating innovative bottlebrush polymers for various applications, many advancing frontiers in precision medicine.
Notably, his bioprinting initiative recently crafted what could be the first 3D component for on-demand organ printing. Moreover, he has gained a significant Maximizing Investigator’s Research Award of $1.9 million from the National Institutes of Health, marking yet another milestone in his rising career.
The PEG-BB discoveries mark yet another success for the lab.
“We believe this innovation not only promises enhanced treatments for lung diseases with fewer side effects, but it also paves the way for addressing conditions that affect mucosal surfaces throughout the body,” Cai remarked.
The next phase for the lab is to examine PEG-BB’s capability to transport drug molecules across a mucus barrier, utilizing both in vitro and in vivo experiments in mice.
Publication
The paper titled Bottlebrush Polyethylene Glycol Nanocarriers Translocate across Human Airway Epithelium via Molecular Architecture-Enhanced Endocytosis was published on June 27, 2024, in ACS Nano.
This research received support from multiple sources, including 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.
