Pulmonary surfactant and drug delivery: Focusing on the role of surfactant proteins.

Pulmonary surfactant (PS) has been extensively studied because of its primary role in mammalian breathing. The deposition of this surface-active material at the alveolar air-water interface is essential to lower surface tension, thus avoiding alveolar collapse during expiration. In addition, PS is involved in host defense, facilitating the clearance of potentially harmful particulates. PS has a unique composition, including 92% of lipids and 8% of surfactant proteins (SPs) by mass. Although they constitute the minor fraction, SPs to a large extent orchestrate PS-related functions. PS contains four surfactant proteins (SPs) that can be structurally and functionally divided in two groups, i.e. the large hydrophilic SP-A and SP-D and the smaller hydrophobic SP-B and SP-C. The former belong to the family of collectins and are involved in opsonization processes, thus promoting uptake of pathogens and (nano)particles by phagocytic cell types. The latter SPs regulate interfacial surfactant adsorption dynamics, facilitating (phospho)lipid transfer and membrane fusion processes. In the context of pulmonary drug delivery, the exploitation of PS as a carrier to promote drug spreading along the alveolar interface is gaining interest. In addition, recent studies investigated the interaction of PS with drug-loaded nanoparticles (nanomedicines) following pulmonary administration, which strongly influences their biological fate, drug delivery efficiency and toxicological profile. Interestingly, the specific biophysical mode-of-action of the four SPs affect the drug delivery process of nanomedicines both on the extra-and intracellular level, modulating pulmonary distribution, cell targeting and intracellular delivery. This knowledge can be harnessed to exploit SPs for the design of unique and bio-inspired drug delivery strategies.