title: A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) (7-36) is a peptide incretin hormone released from the endocrine L-cells of the intestinal mucosa with unique antidiabetic potential. Due to low absorption efficiency and instability in the gastrointestinal tract, the introduction of orally active GLP-1 is a large challenge. Here we developed a novel silica-based pH-sensitive nanomatrix of GLP-1 (SPN-GLP-1) in order to provide a strategy for oral peptide delivery.
  
  
  METHODS
  SPN-GLP-1 composed of silica nanoparticles and pH-sensitive Eudragit(®) was prepared and characterized by dynamic light scattering, scanning electron microscope, transmission electron microscope, high-performance liquid chromatography, surface analysis, drug release, and so on. Its permeability across the Caco-2 cell monolayer and intestinal mucosa, proteolytic stability against the intestinal enzymes, pharmacokinetics, hypoglycemic effect in the intraperitoneal glucose tolerance test (IPGTT), and primary toxicity were then evaluated.
  
  
  RESULTS
  It was indicated that the nanomatrix system obtained had a unique nanoscale structure and pH-sensitivity in drug release. It displayed a five-fold intestinal mucosa permeability and significantly higher proteolytic stability compared to native GLP-1 (P < 0.001). A longer half-life was observed after oral administration of SPN-GLP-1, and its relative bioavailability was 35.67% in comparison to intraperitoneal GLP-1. Oral delivery of SPN-GLP-1 significantly reduced the blood glucose level and its hypoglycemic effect over intraperitoneal GLP-1 reached 77%. There was no evident toxicity of SPN-GLP-1 found from both animal status and histochemical analysis of gastrointestinal tissues.
  
  
  CONCLUSIONS
  The silica-based pH-sensitive nanomatrix designed and prepared here might be considered as a potential oral delivery system not only for GLP-1, but also for other peptide or macromolecular drugs.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qu
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Lars
authors.initials: L
authors.lastname: Hovgaard
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Wenbin
authors.initials: W
authors.lastname: Dai
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Wang
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D054795:Incretins / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D009928:Organ Specificity; D051381:Rats; D012822:Silicon Dioxide / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D054795:Incretins; D053769:Nanocapsules; D012822:Silicon Dioxide; D052216:Glucagon-Like Peptide 1