Neo-Glycolipid Oximes as Intestinal Permeation Enhancers for Peptide Hormone PYY3-36

Herein, we describe the design and synthesis of 16 neo-glycolipids that are potential permeation enhancers for oral drug delivery of peptide therapeutics. These amphiphilic neo-glycolipids are composed of fatty acids and various carbohydrates (D-glucose, lactose, cellobiose, maltose) via an oxime linker. The ability of the synthesized neo-glycolipids to enhance permeation of fluorescein-labelled dextran (4 kDa) or 3H-mannitol across intestinal epithelium was investigated in vitro using monolayers of human epithelial Caco-2 cells. Their effects were compared with (pre-)clinically known enhancers as reference compounds; sodium salts of octanoic, decanoic, and dodecanoic acid, and sodium salcaprozate (SNAC). Most neo-glycolipids increased the permeation of the model compounds, proving that neo-glycolipids, which possess vastly different properties from the reference compounds, e.g., in terms of clogD and polar surface area, are effective permeation enhancers. The neo-glycolipid based on decanoic acid and glucose was more potent than related compounds based on disaccharides. Significant differences in solubility and cellular compatibility were found for neo-glyolipids based on different carbohydrates. Finally, neo-glycolipids were evaluated as permeation enhancers for the peptide hormone PYY3-36. Glucose- and maltose-derived neo-glycolipids based on decanoic and dodecanoic acid showed promising enhancements in PYY3-36 permeation while maintaining good cellular compatibility, relevant for oral delivery of obesity treatments.