Researchers Design Nanoparticles Able to Pass Mucus Barrier in Lungs
In a report published in the journal Proceedings of the National Academy of Sciences, a team of experts from the Johns Hopkins University Department of Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine and the Federal University of Rio de Janeiro in Brazil demonstrate their recently designed DNA-loaded nanoparticles capable of passing the mucus barrier covering conducting airways of lung tissue. According to the researchers this new strategy may potentially lead to the development of therapeutic genes that can be directly delivered to the lungs to levels appropriate to treat life-threatening lung conditions such as cystic fibrosis (CF), chronic obstructive pulmonary disease and asthma.
“To our knowledge, this is the first biodegradable gene delivery system that efficiently penetrates the human airway mucus barrier of lung tissue,” said in a recent news release study author Jung Soo Suk, Ph.D., a biomedical engineer and faculty member at the Center for Nanomedicine at the Wilmer Eye Institute at Johns Hopkins.
The lung mucus barrier is responsible for protecting bacteria and other foreign agents from infecting lungs. In healthy lung tissues, the inhaled materials are trapped in airway mucus and swept away from the lungs via defeating cilia activities to the stomach to be degraded. However, this protective mechanism also blocks inhaled treatments from attainment their target.
Suk and colleagues worked with small animals and human airway mucus to demonstrate that placing replacement or corrective genes or drug agents inside a biodegradable nanoparticle “wrapper” that patients can inhale is able to pass the mucus barrier. According to the researchers this strategy may one day be used as treatment for severe lung diseases, and since a unique dose might work for many months, patients could have less adverse effects.
This work was build up for previous failed strategies for the treatment of patients with lung conditions. In the case of patients with CF, the majority of the available drugs help to clear infections, however their do not treat the underlying causes. Two recent approved drug agents targeting the CF underlying cause require patients to take medicines every day for their entire lifetime. Moreover, these drugs can only benefit some patients with specific types of mutations.
According to Suk, this research has determined that delivering normal copies of CF-related genes or corrective genes via the mucus-penetrating DNA-loaded nanoparticles could facilitate the long-term production of normal proteins, which may become an effective treatment for the lungs of CF patients, regardless their type of gene mutation.
This strategy may lead to an efficient deliver of those genes to the lungs. Results from previous studies have shown that nonviral, DNA-loaded nanoparticles have positive charge causing the gene to stick to negatively charged biological environments, in this case the lung airways covering mucus.
This means that traditional nanoparticles are too sticky to avoid undesirable off-target interactions during their journey to the target cells. Further, these particles tend to rapidly aggregate in physiological conditions, rendering them too large to penetrate the mesh of airway mucus.
To overcome these limitations the researchers created a method that densely coats the nanoparticles with a nonsticky polymer named PEG, neutralized the charge and produced a nonsticky exterior.
Results showed that these nanoparticles keep their size and rapidly penetrated human airway mucus. The researchers also developed the delivery system biodegradable. The scientists packed the nanoparticles with a gene that makes light-generating proteins once delivered into the target cells, thus providing an efficient gene transfer to the lungs of animals.
The inhaled delivery of the genes via the mucus-penetrating nanoparticles caused an increase in the levels of proteins production. These levels were superior to traditional nonviral platforms. In the study the researchers also demonstrated that the treated lungs lit up for up to four months following a single dosing.
“With one dose, you can get gene expression—i.e., production of therapeutic proteins—for several months,” Suk said, mentioning that the nanoparticles did not cause increased lung inflammation and other adverse side events. According to the researchers more studies with animals are necessary to validate their findings. The authors also mentioned that treatment of human disorders with nanowrapped therapies is years away.