肠道菌群协同化瘀泄浊中药多成分多级释药微囊用于肾纤维化治疗研究

It is generally accepted that development of renal fibrosis is the final common pathway of chronic kidney disease. So halting and preventing the development of renal fibrosis is critical for all kidney disease. Here, therapeutic strategy based on gut-kidney theory and chinese medisine pathology on renal fibrosis was presented, which is “gut microbiota synergize huayu xiezhuo”. In order to fulfill this strategy,pH sensitive, bioadhensive and multi-release oral microcapsule system was stablished. In the Core-shell microcapsule, free drug molecules, emodin(EMO), and emodin/ Tanshinone IIA (Tan IIA ) -loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were encapsuled.The capsules is stable in the acid condition of stomach and the encapsulated EMO molecules can be released due to the decomposition of chitosan/alginate shell under the unique alkaline condition of intestine, which will regulate the gut microbiota. Simultaneously, the co-encapsulated drug-loaded PLGA nanoparticles are also released out, which could provide second sustained-release based on the synergistic effect of drug diffusion and PLGA degradation.With the modification of PEG and CPP on the surface of the nanoparticle,it will achieve both excellent mucus permeation and transepithelial absorption.Thus, EMO and Tan IIA can be absorbed well and exert their sysnergistic effect of “huayu xiezhuo”..The present project will propose a new strategy for renal fibrosis therapy and new oral drug delivery system. Meanwhile, the new idea and new method on sequential drug release and sysnergistic effect of multiple components of Traditional Chinese medicine was also proposed.

肾脏纤维化是慢性肾脏疾病发展到终末期肾衰竭的共同通路，阻断肾纤维化对肾病治疗具有重要意义。鉴于肾纤维化错综复杂的发病机制，本项目拟将“肠-肾轴”学说与肾纤维化中医病机理论相结合，提出“肠道菌群协同化瘀泄浊”的肾纤维化治疗策略。项目拟构建pH敏感、生物黏附性的口服多级释药微囊系统，该微囊同时包封大黄素（EMO）及载有EMO/丹参酮IIA（Tan IIA）可高效穿透黏液和上皮细胞屏障的纳米粒，该体系在胃内环境下稳定，到达肠道后释放EMO调节肠道菌群，修复肠黏膜上皮细胞；同时释放载有经PEG/CPP修饰的EMO/Tan IIA的纳米粒，纳米粒促进EMO/Tan IIA的跨膜转运释放后发挥中药多成分“活血化瘀、泄浊排毒”的协同治疗作用。通过本项目研究为肾纤维化的有效治疗提供新策略，并为新策略的实现构建多级释药载体，为中药多成分的层次化释放及协同作用发挥提供新思路和新方法。

针对肾纤维化病理特点，结合“肠-肾轴”学说和中药多组分治疗优势，本项目提出了一种“肠道菌群协同化瘀泄浊”的肾纤维化治疗策略，构建了一种pH敏感、生物黏附性的包载中药多成分的口服多级释药微囊系统。该微囊为“NANO-IN-MICRO”结构：采用壳聚糖/海藻酸钠微囊包载大黄酸（EMO）和丹参酮IIA（Tan IIA）纳米粒。其中纳米粒经CPP/PEG共修饰，体外试验表明，该纳米粒具有较佳的黏液渗透及上皮细胞穿透能力；体内外研究表明，该微囊具有良好的 pH 敏感及多级释药特征；可在小鼠肠道长时间滞留，并可有效保护其中PEG / CPP共修饰的纳米粒；显著提高了大黄素与丹参酮 IIA的口服吸收。药效学结果表明该多级释药微囊可显著降低UUO大鼠的尿素氮、血肌酐及尿蛋白，改善UUO大鼠肾功能；同时亦可修复肠道黏膜屏障，调节菌群结构，从而有效改善了UUO大鼠肾纤维化。目前该项目研究结果已发表在《Phytomedicine》、《International Journal of Pharmaceutics》、《Acta Pharmaceutica Sinica B》等杂志上，共发表SCI学术论文12篇及核心期刊论文1篇(均标注基金号81873018)，获授权专利1项，培养硕士研究生5名。现已圆满完成课题任务书预期指标。