Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston 02115, USA; Harvard Medical School, 25 Shattuck St, Boston 02115, USA.
Division of Gastroenterology, Boston Children's Hospital, 300 Longwood Avenue, Boston 02115, USA.
J Control Release. 2014 Feb 10;175:72-8. doi: 10.1016/j.jconrel.2013.12.013. Epub 2013 Dec 23.
The incretin hormone Glucagon-like peptide 1 (GLP-1) requires delivery by injection for the treatment of Type 2 diabetes mellitus. Here, we test if the properties of glycosphingolipid trafficking in epithelial cells can be applied to convert GLP-1 into a molecule suitable for mucosal absorption. GLP-1 was coupled to the extracellular oligosaccharide domain of GM1 species containing ceramides with different fatty acids and with minimal loss of incretin bioactivity. When applied to apical surfaces of polarized epithelial cells in monolayer culture, only GLP-1 coupled to GM1-ceramides with short- or cis-unsaturated fatty acids trafficked efficiently across the cell to the basolateral membrane by transcytosis. In vivo studies showed mucosal absorption after nasal administration. The results substantiate our recently reported dependence on ceramide structure for trafficking the GM1 across polarized epithelial cells and support the idea that specific glycosphingolipids can be harnessed as molecular vehicles for mucosal delivery of therapeutic peptides.
肠促胰岛素激素胰高血糖素样肽 1（GLP-1）需要通过注射来治疗 2 型糖尿病。在这里，我们测试了糖脂在细胞内运输的特性是否可以应用于将 GLP-1 转化为适合粘膜吸收的分子。GLP-1 与含有不同脂肪酸的 GM1 种类的细胞外寡糖结构域相连，并且对肠降血糖活性的损失最小。当将其应用于单层培养的极化上皮细胞的顶表面时，只有与具有短链或顺式不饱和脂肪酸的 GM1-神经酰胺偶联的 GLP-1 才能通过胞吞作用有效地穿过细胞并转运至基底外侧膜。体内研究表明，鼻内给药后可吸收粘膜。这些结果证实了我们最近报道的关于 GM1 通过极化上皮细胞运输对神经酰胺结构的依赖性，并支持了这样一种观点，即特定的糖脂可以被用作粘膜传递治疗性肽的分子载体。
