The delivery of therapeutic peptides via the oral route remains one of biggest challenges in the pharmaceutical industry. Recently, we have described an alternative improved drug delivery system for peptide delivery via the oral route, consisting of a lipidic nanocapsule. Despite the striking effects observed, it is still essential to develop strategies to strengthen the nanocarriers’ glucagon-like peptide-1 (GLP-1) secretory effect of the nanocarrier and/or prolong its antidiabetic effect in vivo to facilitate its translation into the clinic. For this purpose, we developed and compared different fatty acid-targeted lipid and polymeric nanoparticles and evaluated the L cell stimulation induced by the nanocarriers in murine L cells in vitro and in normal healthy mice in vivo. We further examined the antidiabetic effect in vivo in an obese/diabetic mouse model induced by high-fat diet feeding and examined the effect of the oral administration frequency. Among the tested nanocarriers, only lipid-based nanocarriers that were surface-modified with DSPE-PEG₂₀₀₀ on the surface were able to significantly strengthen the biological effect of the nanocarriers. They increased endogenous GLP-1 levels up to 8-fold in vivo in normoglycemic mice. Moreover, they effectively prolonged the in vivo antidiabetic effect by normalizing the plasma glucose levels in obese/diabetic mice following long-term treatment (one month). Ultimately, the targeted nanocarriers were as effective when the administration frequency was reduced from once daily to once every other day.

通过口服途径递送治疗性肽仍然是制药工业中的最大挑战之一。最近，我们已经描述了一种替代的改进的药物递送系统，其用于通过口服途径的肽递送，其由脂质纳米胶囊组成。尽管观察到了惊人的效果，但仍然有必要制定策略以增强纳米载体的胰高血糖素样肽-1（GLP-1）分泌作用和/或延长其体内的抗糖尿病作用，以利于其转化为临床。为此，我们开发并比较了不同的以脂肪酸为靶标的脂质和聚合物纳米颗粒，并评估了纳米载体在体外和正常健康小鼠的鼠L细胞中诱导的L细胞刺激体内。我们进一步检查了在高脂饮食喂养诱导的肥胖/糖尿病小鼠模型中的体内抗糖尿病作用，并研究了口服给药频率的作用。在测试的纳米载体中，只有在表面上用DSPE-PEG ₂₀₀₀表面修饰过的基于脂质的纳米载体才能显着增强纳米载体的生物学作用。他们在正常血糖小鼠体内将内源性GLP-1水平提高了8倍。而且，它们有效地延长了体内长期治疗（一个月）后，通过使肥胖/糖尿病小鼠的血浆葡萄糖水平正常化来实现抗糖尿病作用。最终，当施用频率从每天一次降低到每隔一天一次时，靶向纳米载体同样有效。