基于“药载共济”效应构建桑葛提取物复合硒纳米系统用于糖尿病治疗研究

Diabetes is a commonly occured metabolic disease and has high hazards of health. Although western medicine therapy can control the blood glucose levels, but patients need to take medication throughout their life (s.c. insulin or oral antidiabetics). It has been proved that traditional Chinese medicine remedy not only can effectively control the symptom “three polys and one little" of diabetes, can also reconstruct the body function and restore the sugar homeostasis of body. In order to explore more efficient approach for diabetes treatment, we carried out a preliminary literature review and experimental research, and found that oral administration of Folium mori and Radix Puerariae extracts (shorted as SGE) combined with selenium supplement has significant hypoglycemic effect. In view of the low toxicity of Chinese medicine and thoroughness in anti-diabetes, we have reason to speculate that it is of high value to make use of compound preparation with hypoglycemic herb extracts and selenium for diabetes treatment. This study aims to construct a selenium-contained oral nano-preparation loading SGE, and to further enhance the therapeutic efficacy of diabetes by the absorption-promotional function of nanocarriers and hypoglycemic activity of SGE as well as the selenium’s synergistic effect in treatment. We intend to prepare DOTAP-modified SGE-NPs (SGE-loaded PLGA nanoparticles) through a solvent-diffusion technique. On the basis of SGE-NPs, glutathione (GSH) is utilized to reduce Na2SeO3 in the nanosuspesion system to fabricate complex selenium nanoparticles (SGE-SeNPs), thus integrating SGE and selenium into a nano-formulation. And then, we shall study the hypoglycemic action of SGE-SeNPs and mechanism thereof. In this project, the therapeutic potential of "drug-carriers" synergy in diabetes treatment will be explored fully.

糖尿病是常见的代谢性疾病，具有较高的危害性。虽然西医治疗可控制体内血糖水平，但患者需终身用药。实践证明，中医药治疗不仅能有效控制糖尿病“三多一少”症状，还可重构机体功能、恢复人体糖代谢平衡。为了探索更高效的糖尿病治疗方法，我们进行了前期文献调研和初步实验研究，发现口服桑叶和葛根提取物和硒剂具有显著的降血糖作用。鉴于中药的低毒性和治疗的彻底性，有理由推测中药降糖成分和硒的复方制剂具有潜在的糖尿病治疗价值！本项目旨在构建一种载中药降糖成分的含硒口服纳米制剂，利用纳米载体的促吸收作用和中药降糖及硒的协同作用进一步改善糖尿病治疗效果。本项目拟通过溶剂扩散法制备载桑叶和葛根提取物的DOTAP修饰阳离子PLGA纳米粒，在此基础上通过谷胱甘肽还原Na2SeO3生成复合硒纳米粒，实现中药降糖成分和硒的有机结合。进而进行桑葛提取物硒纳米粒的体内降糖及作用机制研究，探讨“药载共济“效应在糖尿病治疗上的意义。

糖尿病是一种难以治愈的代谢性疾病，发病率呈逐年增加趋势。口服降糖药和皮下注射胰岛素是现阶段糖尿病治疗的主要手段，但以血糖控制为主的治疗策略治标不治本，不能彻底改变糖尿病治疗现状。本项目利用中医药在治疗糖尿病上面的诸多优势，如降糖作用温和、毒副作用小等，设计开发了一种或许能够实现标本兼治的硒纳米治疗系统。本项目构建的硒纳米粒，不仅具有载药作用，也同时兼具协同抗糖尿病作用，具有一定的“药载共济”效应。硒和抗糖尿病中药活性成分的有效整合，既解决了药物传递问题，又解决了治疗作用靶点单一问题。本项目系统研究了载桑葛提取物硒纳米粒的制备、定性与表征、药物释放、制剂稳定性、药动学与药效学、口服递药机制和抗糖尿病作用机制。本项目在课题组成员和研究生的不懈努力下，取得了一定的研究成果。如发现桑葛提取物载入硒层积纳米粒后具有一定的降血糖作用，这是首次发现桑叶和葛根配伍提取物在体内具有降糖作用，尽管降糖作用不及胰岛素，但降糖作用温和持久。在硒纳米粒口服药物传递机制方面，我们发现网格蛋白和小窝蛋白介导的内吞是其主要的摄取机制。在硒纳米粒抗糖尿病作用机制方面，我们发现载桑葛提取物硒纳米粒可以通过抗氧化、恢复胰岛功能和促进脂肪细胞对葡萄糖的消耗机制起到抗糖尿病的作用。此外，在本自然科学基金的资助下，本课题组也进行了一系列的关于富硒纳米粒药物传递方面的研究，共发表SCI论文9篇（II区7篇）。本研究起到了对传统中医药与现代制剂的融合作用，补硒疗法和抗糖尿病中药的结合为糖尿病治疗提供了一种新的思路！