Contribution of surface-associated membranes to pulmonary surfactant-mediated drug delivery.

Abstract

Pulmonary surfactant (PS) exhibits unique composition and biophysical properties to transport different type of therapeutic molecules. This has motivated its study as an efficient delivery vehicle for various drugs, especially molecules with hydrophobic character. PS is synthesized and secreted to the alveolar space by type II pneumocytes, where it spontaneously adsorbs into the air-liquid interface to reduce the surface tension. The adsorbed surfactant film is constituted by an interfacial monolayer with multi-layered membranes associated to it. Surfactant proteins SP-B and SP-C are responsible for maintaining the contact between these reservoirs and the interfacial layer. In order to study whether the multi-layered and multi-vesicular structures spread along the interface together with the interfacial monolayer, potentially serving as a vehicle for drugs, we have designed a novel vehiculization surface balance that connects a donor with a recipient compartment through a long interfacial pathway. Typically, the vehiculization of drugs mediated by PS has been evaluated in vitro by setups that combine different compartments through interfacial paper bridges. By incorporating a lipid fluorescent probe and the model hydrophobic drug Budesonide (BUD) into a porcine derived PS or into proteo-lipid vesicles, we determined that the amount of material transferred from a donor to a recipient compartment was substantially reduced due to the barrier imposed by the paper bridge. The bridge reduced the spreading to a simpler interfacial layer, while our novel setup reveals that a larger three-dimensional layer of liquid may facilitate the spreading of associated membranes and surfactant/drug complexes. We have determined that the three-dimensional structures associated to the interfacial layer spread along the air-liquid interface and entail an important contribution to the transport of lipids and drugs in surfactant-mediated delivery.