Schematic of polymer nanoparticle delivery to the developing lungs of fetuses.
Schematic of polymer nanoparticle delivery to the developing lungs of fetuses.

Polymer nanoparticles that can deliver active agents to the developing lungs of a fetus could lead to treatments for congenital disorders in the future, according to researchers from Yale University [Ullrich et al., Acta Biomaterialia (2021),].

“There are several diseases… that can be diagnosed before birth and the best window to treat them and allow the lung to develop normally is before the fetus takes its first breath,” explains Sarah J. Ullrich, first author of the study. “In severe lung disease, if this therapy is applied after birth it may be too late.”

Delivering drugs or gene editing technologies in utero, combined with prenatal testing and diagnosis, could offer the ability to treat disorders such as cystic fibrosis and congenital diaphragmatic hernia, halting lung damage in the fetus before it becomes permanent. The team from Yale has already shown that polymer nanoparticles can accumulate in tissue, with size affecting their biodistribution. Now the researchers have compared three widely used biodegradable and biocompatible polymers, poly(lactic-co-glycolic) acid (PLGA), polylactic acid (PLA), and poly(amine-co-esters) (PACEs).

Both PLGA and PLA are biodegradable and biocompatible, but PLA is more limited in terms of its usefulness because it is highly hydrophobic. To overcome this shortcoming, the team created PLA nanoparticles treated with poly(ethylene glycol) or PEG, which increases hydrophilicity, reducing interactions with biomolecules and increasing circulation time in the body. The third class of polymer investigated, cationic PACE nanoparticles, are particularly promising for delivering nucleic acids. Nanoparticles of each type of polymer, in varying sizes, were introduced into either the amniotic fluid or intravenously to be taken up into the lungs of fetal mice. IV injection proved the most effective means of introducing nanoparticles, the team found.

“Particles that are injected into the amniotic space are diluted by the amniotic fluid so the relative dose that gets to the lungs is lower than a comparable dose injected systemically,” explains Ullrich.

Fluorescent tagging enabled the researchers to track in which tissues the nanoparticles accumulate.  They found that PACE particles are taken up primarily by epithelial and endothelial cells, while larger particles are taken up by cells less overall. Surface treatment with PEG, known as PEGylation, appears to have a positive effect on cell uptake regardless of polymer or particle sizes. The researchers suggest that PEGylation improves the solubility and dispersion of nanoparticles, increasing circulation time, neutralizing nanoparticle charge, and boosting diffusion. Since PEGylated nanocarriers are delivered more effectively to pulmonary endothelial cells, this could offer a route to treating congenital heart defects.

“We now need to test the safety and efficacy of delivering therapeutic agents in preclinical animal models and larger animal models,” says Ullrich.