Many treatments for chronic lung diseases rely on the ability of therapeutic agents to be delivered directly to the pulmonary lining of obstructed lungs. One way to improve drug distribution within the lung is to add surfactants to the drug formulations. These surfactants induce a surface tension gradient, which causes drug to spread across the airway surface liquid. This spreading, known as Marangoni flow, allows therapeutic agents to travel deep into the lung and to coat the entire airway surface evenly. Surfactant-aided pulmonary drug delivery methods would benefit from the use of the lung’s own natural surfactants (phospholipids), rather than conventional synthetic surfactants. However, there is no previous experimental work to show that phospholipid dispersions can induce Marangoni flow.
In this work, we use the phospholipid dimyristoylphosphatidylcholine (DMPC) as a spreading agent on a water subphase. Because phospholipids are not water soluble, the DMPC is dispersed as a vesicle suspension in water so that it may be delivered to the aqueous airway lining. Two methods of creating dispersions of DMPC are used in this work; one creates small, unilamellar vesicles, and the other creates multilamellar vesicles. Although these dispersions themselves have reduced surface tensions as compared with water, when they are delivered as microliter drops onto a water supbase, neither has any ability to cause spreading. This suggests that these dispersions do not release lipids to the water surface, and, therefore, cannot induce Marangoni flow. Here, we will show that aerosolization of these DMPC dispersions does release lipids. When this aerosolized DMPC dispersion is deposited onto a water subphase, it creates the surface tension gradient needed to induce Marangoni flow and cause spreading.
The process of aerosolization forces liquid through a vibrating mesh in order to create a fine mist of droplets. In our work, aqueous DPMC dispersion is aerosolized directly and non-uniformly onto water in order to observe the aerosolized lipid’s spreading ability. The spreading ability is detected in two ways: 1) by the distance indicator particles on the surface move after aerosol deposition, and 2) by the decrease in surface tension outside of the deposition area. Both movement of indicator particles and lowering of surface tension are observed upon DMPC aerosol deposition. The aerosolized DMPC lowers the surface tension of water by over 40mN/m and moves polystyrene indicator beads to the end of our 10cm experimental trough. This is on par with, or even greater than, the spreading seen by synthetic surfactants such as sodium dodecyl sulfate and tyloxapol.
We hypothesize that the aerosolization process breaks open the phospholipid vesicles within the dispersion and allows lipid molecules to be stored on the droplet surfaces. When these droplets land, they populate the air-liquid interface with lipid molecules, forming a monolayer. Evidence for this is obtained in ellipsometry trials that show a monolayer thickness of DMPC after aerosol deposition. This DMPC monolayer induces the surface tension gradient needed to cause Marangoni flow, which, in turn, drives the particles across the water surface. Our work shows that aerosolization enables the use of natural phospholipids, which are not effective spreading agents when administered in the form of vesicle dispersions, to create Marangoni flow and enhance drug dispersal in the pulmonary airways.