Liposomes Containing Tetraether Lipids and Cell‐Penetrating Peptides as Platform Technology for Oral Delivery of Peptides: A Comparative Study on GLP‐1 Analogs

ABSTRACT In this study, the potential of liposomes containing tetraether lipids (TELs) and cell‐penetrating peptides (CPPs) as a platform technology for oral delivery of peptides, using the glucagon‐like peptide 1 (GLP‐1) analogs semaglutide, exenatide, and dulaglutide as model compounds, was investigated. As this technology was proven effective in vitro and in vivo in mice and dogs for a small, hydrophilic glycopeptide drug (vancomycin) before, the focus of this study was to evaluate the applicability for peptide therapeutics with higher molecular weight (exenatide–4186.8 Da, semaglutide–4113.6 Da, and dulaglutide–59670.6 Da) and different physico‐chemical properties (semaglutide). For this purpose, liposomal formulations were prepared by dual centrifugation and characterized by size, polydispersity index, zeta potential, morphology, and encapsulation efficiency. All GLP‐1 analogs liposomal formulations revealed promising liposomal characteristics and were subsequently investigated with respect to uptake on colon‐carcinoma‐2 (CaCo‐2) cells and biocompatibility. Besides the high biocompatibility, a highly increased uptake of all three GLP‐1 analogs encapsulated into the liposomes containing TELs and CPPs in comparison to the free compound could be demonstrated on CaCo‐2 cells. These findings highlight the great potential of this liposomal technology for oral delivery of peptide therapeutics in general.