Strengthening peptide-based drug activity with novel glyconanoparticle

• Published in: PloS one Vol. 13; no. 9; p. e0204472
• Main Authors: Lewicky, Jordan D., Martel, Alexandrine L., Fraleigh, Nya L., Boraman, Amanda, Nguyen, Thi M.-D., Schiller, Peter W., Shiao, Tze Chieh, Roy, René, Le, Hoang-Thanh
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.09.2018; Public Library of Science (PLoS)
• Subjects: Addictions; Animals; Biology; Biology and Life Sciences; Cancer therapies; Chromatography; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Contaminants; Degradation; Drug delivery; Drug Delivery Systems; Drug Stability; Drug therapy; Drugs; Dynorphins - administration & dosage; Dynorphins - blood; Dynorphins - pharmacokinetics; Entrapment; Enzymes; Female; Glycolipids; Glycolipids - administration & dosage; Glycolipids - chemistry; Health sciences; High performance liquid chromatography; Immunosuppressive agents; In Vitro Techniques; Kinases; Laboratories; Linearity; Liposomes; Liposomes - administration & dosage; Liposomes - chemistry; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Medicine and Health Sciences; Metabolism; Muramyl dipeptide; Nanoparticles; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Narcotic Antagonists - administration & dosage; Narcotic Antagonists - blood; Narcotic Antagonists - pharmacokinetics; Narcotics; NOD2 protein; Opioid receptors (type kappa); Peptides; Peptides - administration & dosage; Peptides - blood; Peptides - pharmacokinetics; Permeability; Physical Sciences; Plasma; Protein Stability; Proteolysis; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa - antagonists & inhibitors; Research and Analysis Methods; Self-assembly; Spectrometry, Mass, Electrospray Ionization; Stability analysis; Structural stability; Canada; Ontario Canada; Montreal Quebec Canada; Quebec Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0204472

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.