脂肪细胞特异性核酸适体修饰包封大黄素PLGA-PEG纳米粒靶向治疗肥胖及机理研究

Excess glucocorticoid (GC) in the circulation or local tissue can leads to obesity and diabetes. 11β-HSD1 plays an important role in transformation of localized inactive GC into active GC. Inhibition of 11β-HSD1 in white adipose tissue is effective in treating obesity, improve glucose metabolism and lipid abnormalities, thus becoming a new target for the treatment of obesity. Emodin is a potent inhibitor of 11β-HSD1, but without tissue specificity. We previously have selected an aptamer named Adipo 8 specific for white adipose tissue using Cell-SELEX technology. Based on it, we constructed adipo 8/PLGA-PEG/emodin by embedding emodin into PLGA-PEG nanoparticle modified with adipo 8 for targeted delivery of emodin to white adipose tissue for the treatment of obesity. To this end, we employed high-fat diet -induced obese mice (DIO) animal model to study the target and the effects of adipo 8/PLGA-PEG/emodin on obesity. We will study the mechanism from the inhibition of adipocyte adipogenic differentiation in the cell and animal level. In this study, we first combined aptamer and nanotechnology to modify emodin for specific inhibition of 11β-HSD1 in white adipose tissue, providing a new way for the targeted therapy of obesity.

糖皮质激素（GC）过剩导致肥胖、糖尿病等异常与其循环水平或局部组织的量增加有关。11β-HSD1使无活性的GC转变为有活性的GC发挥作用，抑制白色脂肪组织11β-HSD1能有效治疗肥胖、改善糖脂代谢，已成为治疗肥胖新靶点。中药大黄素是强效11β-HSD1抑制剂，但无组织特异性。我们用Cell-SELEX筛选了一条仅与白色脂肪组织高特异性结合的核酸适体Adipo8。基于此，我们拟用PLGA-PEG纳米粒包封大黄素修饰Adipo8,构建adipo8/PLGA-PEG/大黄素复合载体，使大黄素特异性抑制白色脂肪组织11β-HSD1达到靶向治疗肥胖的目的。利用高脂饮食构建肥胖小鼠模型，从细胞和动物水平研究adipo8/PLGA-PEG/大黄素复合载体对白色脂肪组织的靶向性、抑制成脂的作用及机制。首次使用核酸适体联合纳米技术修饰大黄素特异性抑制白色脂肪组织11β-HSD1，为肥胖的靶向治疗提供新途径。

糖皮质激素（GC）过剩导致肥胖、糖尿病等异常与其循环水平或局部组织的量增加有关。 11β-HSD1使无活性的GC转变为有活性的GC发挥作用，抑制白色脂肪组织11β-HSD1能有效治疗 肥胖、改善糖脂代谢，已成为治疗肥胖新靶点。中药大黄素是强效11β-HSD1抑制剂，但无组织特异性。我们在前期实验中用Cell-SELEX筛选了一条仅与白色脂肪组织高特异性结合的核酸适体Adipo8。 在本项目中，我们用PLGA-PEG纳米粒包封大黄素修饰Adipo8,成功的构建了adipo8/PLGA-PEG/大黄素复合载体，并进行了载药量，释放效率，稳定性的研究。接着我们从细胞水平验证了复合载体能够特异性的降低脂肪细胞的脂滴含量，下一步，我们利用高脂饮食构建肥胖小鼠模型，从动物水平研究复合载体对白色脂肪组织的靶向性、抑制成脂的作用及相关机制。我们首次使用核酸适体联合纳米技术修饰大黄素特异性抑制白色脂肪组织11β-HSD1，为将来肥胖的靶向药物的开发和肥胖的治疗提供了理论依据和新途径。