Cell penetrating liposomes for the oral delivery of peptide drugs
Final Report 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. In this grant application, a liposomal nanocarrier combining two self-reliant strategies to overcome these delivery barriers was developed. This approach enabled to design a nanocarrier system with synergistic properties: tetraether lipids derived from archaea were incorporated into liposomes to provide the particles with the stability required to traverse the stomach. However, anisotropy measurements showed that incorporation of 5 mol-% GCTE had no impact on the rigidity of the lipid membrane, suggesting that other mechanisms underlie its GIT-protective properties. When the surface of the resulting inert particles was modified with cell-penetrating peptides, mucosal permeation could be achieved. The designed nanocarrier was proven effective by the high mucosal uptake of the glycopeptide antibiotic vancomycin in Ussing chamber studies. Efficacy in vivo was demonstrated in naïve rats, where a highly increased oral bioavailability was obtained for vancomycin, a drug known to be minimally absorbed. In contrast, administration of liposomes with single modification (tetraether lipids) in this case led to a substantially lower bioavailability. Therapeutic efficacy was proven by the antimicrobial activity of vancomycin in a Galleria mellonella and a systemic infection mouse model. Subsequently, the translation of this nanocarrier system from rodent models into higher mammals was proven successful in beagle dogs by a 3.64 -fold increase in oral bioavailability of vancomycin incorporated into the nanocarrier in comparison to the free drug. In contrast, using the peptide drug exenatide as one further model active pharmaceutical ingredient, a concentration-dependent increase in liposomal size and polydispersity was observed, while the CPPs had no impact on membrane fluidity. A concentration-dependent interaction between the positively charged CPP and exenatide seems to be the cause of the interaction. This interaction could also be observed in the morphology and size of the liposomes obtained by cryo-TEM images. Due to the incompatibility caused by the use of CPPs, only liposomes with 5 mol% GCTE were tested in the in vivo rat model. The data obtained showed an improved bioavailability by 18-fold in comparison with orally administered carrier-free exenatide. Compared to the Byetta® formulation, the liposomal carrier system led to a relative bioavailability of approximately 2%. These results illustrate that the nanocarrier system itself has to be adopted to the corresponding peptide drug. However, a strong increase in oral bioavailability could be shown for both model drugs. These findings demonstrate that this nanocarrier delivery strategy might boost the oral application of macromolecular drugs in general.
Publications
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(2020). Coating of PLA-nanoparticles with cyclic, arginine-rich cell penetrating peptides enables oral delivery of liraglutide. Nanomedicine: Nanotechnology, Biology and Medicine, 24, 102132
Uhl, P., Grundmann, C., Sauter, M., Storck, P., Tursch, A., Özbek, S., ... Fricker, G. & Mier, W.
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(2021). Overcoming the Mucosal Barrier: Tetraether Lipid‐Stabilized Liposomal Nanocarriers Decorated with Cell‐Penetrating Peptides Enable Oral Delivery of Vancomycin. Advanced Therapeutics, 4, 2000247
Uhl, P., Sauter, M., Hertlein, T., Witzigmann, D., Laffleur, F., Hofhaus, G., ... Fricker, G. & Mier, W.
