Abstract
The therapeutic application of peptide-based drugs is significantly limited by the rapid proteolytic degradation that occurs when in blood. Encapsulation of these peptide structures within a delivery system, such as liposomes, can greatly improve both stability and target delivery. As part of our work focused on novel ambiphilic mannosylated neoglycolipids as targeted drug delivery systems, we have developed a C14-alkyl-mannopyranoside that forms self-assembled monodisperse liposomes. Herein, these glycoliposomes are investigated as a potential method to improve the plasma stability of peptide-based drugs. Reversed phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry (MS) methods were developed to assess the in vitro plasma stability of two structurally diverse peptides, including the kappa opioid receptor selective antagonist dynantin, and the NOD2 innate immune receptor ligand muramyl dipeptide (MDP). The RP-HPLC methods developed were able to resolve the peptides from background plasma contaminants and provided suitable response levels and linearity over an appropriate concentration range. Both compounds were found to be significantly degraded in rat plasma. Increasing degrees of both entrapment and stabilization were noted when dynantin was combined with the C14-alkyl-mannopyranoside in increasing peptide:glycoside ratios. The combination of MDP with the glycolipid also led to peptide entrapment, which greatly improved the plasma stability of the peptide. Overall, the results clearly indicate that the stability of peptide-based structures, which are subject to degradation in plasma, can be greatly improved via entrapment within C14-alkyl-mannopyranoside-bearing glycoliposomes.
Highlights
Peptides have low toxicity, high specificity and high affinity to their targets, making them interesting molecules for drug development [1,2,3,4]
An optimized reverse phase gradient HPLC method was developed for the analysis of dynantin plasma stability based on the previously reported methods [43]
Three degradation products have been identified in the crude mixture ([M-H]- = 581.300 from [(2S)-Mdp-G-G-F-L-OH], [M-H]- = 737.404 from [(2S)-MdpG-G-F-L-R-OH], [M-H]- = 893.509 from [(2S)-Mdp-G-G-F-L-R-R-OH]) which result from proteolytic cleavage centered around and in between the two sequential arginine residues
Summary
Peptides have low toxicity, high specificity and high affinity to their targets, making them interesting molecules for drug development [1,2,3,4]. The specific roles of these authors are articulated in the ‘author contributions’ section
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