Intrapulmonary Spreading of Pharyngeally Instilled Liquids: Impact of Nanoparticle Concentration and PEG Lubrication in Polymer Lung Surfactant Solutions

Abstract

The efficacy of surfactant replacement therapy (SRT) depends on the effective delivery of active ingredients─therapeutic lung surfactant (LS), specifically polymer lung surfactant (PLS) nanoparticles in this study─to their target site, the alveoli, in the lungs. This study examines how PLS concentration affects the spreading and distribution of PLS solutions in mouse lungs. A constant volumetric dose (∼80 μL, 4 mL/kg body weight) of PLS solutions at three polymer concentrations (0.6, 6.0, and 60 mg/mL in normal saline) was pharyngeally instilled into acid-injured mouse lungs, and X-ray computed tomography (CT) imaging was used for quantitative analysis. To enhance X-ray contrast, a nontoxic amount of the water-soluble contrast agent Iohexol (50 mg I/mL) was added to the PLS solution. Three-dimensional (3D) tomographic analysis revealed significant concentration-dependent differences in PLS distribution within the lungs. Mice receiving the lowest PLS concentration exhibited a notably higher increase in lung pixel intensity (gray value) compared to those at higher concentrations, indicating greater spreading of PLS into deeper lung regions. Simple calculations suggest this is likely due to lower solution viscosity at lower PLS concentrations, a factor previously overlooked in LS formulation design. Additionally, we investigated whether adding a small amount (0.1 or 1.0 mg/mL) of low-molecular-weight (1 kDa) poly(ethylene glycol) (PEG) to the PLS solution could further enhance spreading. Results showed that PEG significantly improved PLS distribution, particularly at higher PLS concentrations, likely due to interfacial lubrication induced by PEG homopolymers. This PEG-based enhancement strategy may also improve the delivery of commercial phospholipid-based LS formulations.

Keywords: block copolymer micelle; intrapulmonary spreading; liquid instillation; lung surfactant; poly(ethylene glycol); poly(styrene)−poly(ethylene glycol); pulmonary distribution; viscosity.