Elucidating structure of endogenous phospholipids on in vivo absorption of octreotide following lung administration

Phospholipids as endogenous pulmonary components have received extensive attention on promoting the transmembrane absorption of peptides and proteins. However, considering their diversified structure, influence of phospholipid structural characteristics on drug absorption across lung epithelial cells, together with the underlying absorption-promoting mechanisms, remain unclear. Therefore, in this study, taking octreotide as a model drug, phospholipids with different "tail" and "head" structures were adopted in the form of blank liposomes to investigate their structural characteristics on drug absorption utilizing both 3D Transwell cell models and Sprague Dawley rats. It was demonstrated that indeed the absorption-enhancing capacity of phospholipids was their structure-dependent. Among the tail (non-polar) structures, a moderately increased alkyl chain length could facilitate drug absorption across the pulmonary epithelium, with the highest enhancement ratio observed for Dipalmitoyl Phosphatidylcholine (DPPC) containing a palmitoyl group of 16 carbons, and its apparent permeability coefficient (P_app) increased 2.4 times compared to octreotide solution. Among the head (polar) structures, charged functional groups could contribute to better drug permeation, and Dipalmitoyl Phosphatidylserine (DPPS) containing a protonated amino (NH₃⁺) and a deprotonated carboxyl (COO^-) exhibited a 4.6-fold increase in P_app compared to octreotide solution. Mechanism studies disclosed a paracellular pathway-mediated drug transport across lung epithelial cells. In summary, phospholipids can serve as biosafe absorption enhancers for pulmonary drug delivery, with the extent depending on their structure, which could provide a theoretical basis for pulmonary delivery of macromolecules for systemic absorption.