Abstract
BackgroundExenatide (EXT), the first glucagon-like peptide-1 receptor agonist, has been approved as an adjunctive therapy for patients with type 2 diabetes. Due to EXT’s short half-life, EXT must be administrated by continuous subcutaneous (s.c.) injection twice daily. In previous studies, many studies on EXT loaded into polymer materials carriers for sustained release had been reported. However, these carriers have some defects, such as hydrophobicity, low surface energy, low mechanical strength, and poor chemical stability. Therefore, this study aims to develop a novel drug delivery system, which is EXT loaded into well-ordered hexagonal mesoporous silica structures (EXT-SBA-15), to control the sustainability of EXT.MethodsSBA-15 was prepared by hydrothermal method with uniform size. Morphology of SBA-15 was employed by transmission electron microscopy. The pore size of SBA-15 was characterized by N2 adsorption–desorption isotherms. The in vitro drug release behavior and pharmacokinetics of EXT-SBA-15 were investigated. Furthermore, the blood glucose levels of diabetic mice were monitored after subcutaneous injection of EXT-Sol and EXT-SBA-15 to evaluate further the stable hypoglycemic effect of EXT-SBA-15.ResultsEXT-SBA-15 showed a higher drug loading efficiency (15.2 ± 2.0%) and sustained-release features in vitro. In addition, pharmacokinetic studies revealed that the EXT-SBA-15 treatment group extended the half-life t1/2(β) to 14.53 ± 0.70 h compared with that of the EXT solution (EXT-Sol) treatment group (0.60 ± 0.08 h) in vivo. Results of the pharmacodynamics study show that the EXT-SBA-15 treatment group had inhibited blood glucose levels below 20 mmol/L for 25 days, and the lowest blood glucose level was 13 mmol/L on the 10th day.ConclusionsThis study demonstrates that the EXT-SBA-15 delivery system can control the sustainability of EXT and contribute to improve EXT clinical use.Graphical abstract
Highlights
Exenatide (EXT), the first glucagon-like peptide-1 receptor agonist, has been approved as an adjunctive therapy for patients with type 2 diabetes
EXT shares approximately 53% sequence homology with the mammalian glucagon-like peptide-1 (GLP-1), which exhibits obvious advantages developed as a glucoselowering agent with similar functions as GLP-1 [3, 4]
Peptides and proteins loading into SBA-15 avoid stressful procedures that can protect the molecules from bioinactivation, and the stable inorganic oxide framework of mesoporous silica nanoparticles shelters the peptides and proteins from chemical and thermal exposure and harmful species; the electrochemical activity of proteins and peptides would be retained or even increased
Summary
Exenatide (EXT), the first glucagon-like peptide-1 receptor agonist, has been approved as an adjunctive therapy for patients with type 2 diabetes. Many studies on EXT loaded into polymer materials carriers for sustained release had been reported These carriers have some defects, such as hydrophobicity, low surface energy, low mechanical strength, and poor chemical stability. The US FDA has approved a long-acting formulation of EXT dispersed in poly-(D,Llactide-co-glycolide) polymer microspheres in 2012 [10] These polymer-material carriers have defects, such as hydrophobicity, low surface energy, low mechanical strength, and poor chemical stability. We selected well-ordered hexagonal mesoporous silica structures (SBA-15) to load EXT This drug carrier material presents several beneficial properties for sustainedrelease drug delivery, including controllable size and pore morphology to obtain the desired rate of drug release, large internal surface area to allow the adsorption and delivery of high drug payloads within the nanopores, proper in vivo stability preventing premature drug degradation, biodegradability and biocompatibility [11,12,13,14]. Studies on EXT loaded into SBA-15 are few
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