Overcoming the Mucosal Barrier: Tetraether Lipid‐Stabilized Liposomal Nanocarriers Decorated with Cell‐Penetrating Peptides Enable Oral Delivery of Vancomycin

Abstract

Despite the high medical need for oral peptide delivery, instability in the gastrointestinal tract and low mucosal permeation still impede this preferred route of administration. Herein, a liposomal nanocarrier combining two self‐reliant strategies to overcome these delivery barriers is reported. This approach enables the design of a nanocarrier system with synergistic properties: tetraether lipids derived from archaea are incorporated into liposomes to provide the particles with the stability required to traverse the stomach. When the surface of the resulting inert particles is modified with cell‐penetrating peptides, mucosal permeation can be achieved. The designed nanocarrier is proven effective by the high mucosal uptake of the glycopeptide antibiotic vancomycin in Ussing chamber studies. Efficacy in vivo is demonstrated in naïve rats, where a highly increased oral bioavailability is obtained for vancomycin, a drug known to be minimally absorbed. In contrast, administration of liposomes with single modification (tetraether lipids) leads to a substantially lower bioavailability. Therapeutic efficacy is proven by the antimicrobial activity of vancomycin in a Galleria mellonella and a systemic infection mouse model. The high oral bioavailability in absence of cytotoxic effects demonstrates that this nanocarrier delivery strategy might boost the oral application of macromolecular drugs in general.

A Nanocarrier Approach for Oral Peptide Delivery: Evaluation of Cell‐Penetrating‐Peptide‐Modified Liposomal Formulations in Dogs

“…Liposomes were prepared by the film method with subsequent dual asymmetric centrifugation using a SpeedMixer (DAC150FVZ Hausschild Engineering GmbH & Co. KG, Hamm, Germany) as described previously. [ 34 ] In brief, the lipids were dissolved in chloroform/MeOH 9:1 v/v to obtain stock solutions (100 m m ). Afterward, the lipid solutions were transferred into Eppendorf tubes to obtain a lipid mixture.…”

“…Liposomes were additionally characterized with NTA, which was performed using a NanoSight NS300 instrument equipped with a 488 nm laser (Malvern Panalytical) as described previously. [ 34 ] In brief, after confirming the absence of particles (cleaning procedure with 0.2 m filtered water), liposome samples diluted in PBS were injected, and videos of 30 s were recorded. A camera level of 15, a detection threshold of 5, and a minimum of 300 completed tracks were used to analyze the average liposome size and size distribution.…”

“…Therefore, liposomal formulations have been frequently investigated in the context of oral delivery. [28][29][30][31][32][33][34][35][36] A promising complementary strategy is the coadministration of cell-penetrating peptides (CPP) as indirect permeation enhancers, which has been successfully used for oral insulin administration in rats. [37] CPPs are characterized by their ability to cross cell membranes efficiently and passively (independently of transporters and receptors), even when bound to large substances.…”

“…Therefore, liposomal formulations have been frequently investigated in the context of oral delivery. [ 28–36 ]…”

Vesicular and Planar Membranes of Archaea Lipids: Unusual Physical Properties and Biomedical Applications

“…In general, hydrolytic enzyme activity is decreased in this order: conventional liposomes > diether archaeosomes > tetraether archaeosomes [ 41 ]. In addition to achieving higher stability in acidic and digestive environments, glyceryl caldityl tetraether (GCTE) archaeosomes coated with cell-penetrating peptides (CPP) can overcome the problem of low mucosal permeation, as evidenced by more effective oral delivery of vancomycin into the liver in mice than naked GCTE archaeosomes [ 68 ] ( Table 1 ).…”