针对糖尿病肾脏疾病（diabetic kidney disease，DKD）的病理特点（肾小球病变合并肾小管-间质病变），结合中药多成分协同作用的优势，本项目提出了基于肾小球-肾小管连环靶向多成分协同作用的治疗策略。基于这一思路，本项目拟设计一种新型核壳型脂质纳米粒系统。该系统以可实现肾近端小管细胞靶向的低分子量壳聚糖（LMWC）-甘草酸接枝共聚物纳米粒为内核，外层包覆可实现肾小球系膜细胞靶向的抗α8整合素抗体修饰的包载大黄酸（RH）的脂质囊，同时凭借肾脏生理过程及脂质纳米粒系统的多重载药及程序释放特征，实现肾小球-肾小管连环靶向递送中药多成分。此外，项目拟从分子、细胞、整体动物水平对脂质纳米粒系统的肾脏靶向性、分子机制、药效学进行综合评价。通过本项目的研究为高效、特异的糖尿病肾脏疾病的治疗提供新策略，并为有效发挥中药多成分协同治疗作用提供新思路和新方法。

According to the pathologic features of diabetic kidney disease (diabetic kidney disease , DKD) (glomerular disease combined with tubules lesions) and advantages of synergies of traditional Chinese medicine-based multi- components, we proposed a new therapeutic strategy based on the glomerular-tubular sequential targeting and synergies of multiple components. Based on this strategy, we plan to design a novel core-shell lipoparticles system(LNPS). In this system, LMWC- GL nanopartieles, targeted to the renal proximal tubule cells as a core, and lipid shell as a shell, which modified by anti-α8 integrin antibody for target the mesangial cells. Combined with the physiological processes of kidney and the multi-payload and sequential release characteristics of LNPS , this system can deliver multi-components to the glomerular and tubules sequentially. In addition, in this project, the kidney targeting specifity, molecular mechanisms, an pharmacodynamic of the LNPS will also be investigated from molecular, cellular and whole animal aspects. Our project will provides a innovative strategy for efficient and specific kidney disease treatment, and develops new ideas and methods for synergistic therapeutic effects of multi-component of Chinese medicine.

慢性肾脏疾病（chronic kidney disease, CKD）已成为全世界的公共卫生问题，在CKD的早期寻求更有效的治疗策略至关重要。针对CKD的病理特点（肾小球病变合并肾小管间质病变），结合中药多成分协同作用的优势，本项目提出了基于肾小球肾小管连环靶向多成分协同作用的治疗策略。项目研究中首先合成了具有肾小管靶向特性的LMWC- GL接枝物，该接枝物可自组装形成LMWC- GL接枝物纳米粒；通过体外细胞实验优化了大黄素/甘草酸最佳摩尔比，以具有肾小球细胞靶向性的抗α8整合素抗体为配基，以LMWC- GL接枝物为内核，制备了抗体修饰的双载药脂质纳米粒；采用FITC标记LMWC-GL接枝物，研究了肾近端小管上皮细胞HK-2对接枝物的摄取；采用DIL标记双载药免疫脂质体，研究了肾小球系膜细胞HBZY-1对双载药免疫脂质体的摄取情况，验证了免疫脂质纳米粒对肾小球系膜细胞的靶向特性；建立了大鼠血液-肾脏同步微透析取样技术，研究了甘草酸对大黄酸肾脏渗透影响及大黄酸纳米粒肾脏靶向渗透性能；评价了双载药免疫脂质纳米粒的肾脏靶向特性；分别以糖尿病肾病小鼠及UUO小鼠为动物模型，研究了双载药脂质纳米粒对慢性肾脏疾病的治疗作用，同时采用体外细胞实验模型研究了双载药脂质纳米粒的作用机制。本项目完成了主要预定目标。构建了具有肾脏靶向递药性能负载中药多成分的双载药免疫脂质纳米粒；体外细胞实验表明，该脂质纳米粒具有肾小管及肾小球系膜细胞特异靶向性；体内动物实验表明该脂质纳米粒可显著降低尿素氮、血肌酐及尿蛋白，显著改善db/db小鼠肾功能；同时亦可通过下调α-SMA、Col-1、FN等蛋白抑制细胞转分化，从而有效改善UUO小鼠肾间质纤维化。通过项目研究为高效、特异的慢性肾脏疾病的协同治疗策略的发展及应用奠定了实验基础。