Cell penetrating liposomes for the oral delivery of peptide drugs

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The peroral administration of peptides / proteins frequently fails due to their instability in the gastrointestinal tract as well as their extremely low resorption rate. In a previous funding, a liposomal carrier system was tested for peptides / proteins containing Archaea tetraether lipids (TELs). Previous studies have shown an extremely improved stability of such liposomes in the intestinal tract compared to liposomes consisting of conventional phospholipids (Uhl et al., 2016, Parmentier et al., 2011a). Furthermore, peptides could be easily incorporated into the liposomes by means of dual asymmetric centrifugation in a high degree of drug loading (50-70%; Pantze et al., 2014). In bioavailability studies in Wistar rats, a significantly increased bioavailability of macromolecular drugs in TEL liposomes was found as compared to the availability of orally administered drugs [octreotide (MW 1,170 Da); Myrcludex B (MW 5,400 Da) and human growth hormone (MW 23,500 Da)] (Parmentier et al., 2011b, Uhl et al., 2016 and Parmentier et al., 2014). Despite previous achievements, the potential for further improvements still exists. The main goal is to ensure the highest possible resorption rate in the intestine in order to enable a therapeutic application. For this reason, the system established so far has to be further optimized in this follow-up project. For this purpose, the TEL liposomes shall be coated with cell-penetrating peptides (CPPs). Cell-penetrating peptides have already been tested for liposomal intracellular transport (Torchilin et al., 2001), and there exist first data on a possible peroral application (Kamei et al., 2013, 2016). The combination of acid-stable TEL liposomes and cell penetrating peptides showed in our preliminary experiments an increased rate of resorption. Thanks to our novel process, coating can already be carried out during liposome production, which allows omission of later cleaning steps. This enables an efficient, reproducible and cost-effective production on a larger scale. The GLP-1 analogue exenatide consists of 39 amino acids and shall be used as model substance. In this project, a new oral application shall be developed. Exenatide (trade name Byetta) represents a novel class of diabetes therapeutics and the sales were already 650 million dollars in 2007. Meanwhile, a second representative of this class of substances (Liraglutide, Victoza) has also been approved, highlighting the importance of this novel class of substances as a therapy option for diabetes therapy. Exenatide shall be incorporated into TEL liposomes coated with CPPs to investigate the encapsulation efficiency, liposomal size, stability under various conditions, release and process ability to an orally available drug formulation. Finally, a bioavailability study in rats and a pharmacological proof-of-concept trial shall be conducted in a diabetic mouse model.