Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China; Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China.
Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
J Control Release. 2022 Sep;349:401-412. doi: 10.1016/j.jconrel.2022.07.013. Epub 2022 Jul 14.
Renal tubular epithelial cell (RTEC) is a critical target cell for the treatment of acute kidney injury (AKI). Despite various RTEC targeting strategies using ligand modified nanoparticles (NPs) following systemic administration, the nonspecific interaction between NPs and plasma proteins greatly weakens the targeting efficiency as well as the stability of NPs. Herein, celastrol (CLT) was entrapped in D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) forming a CLT-loaded nanocomplex core (CT) with a high loading capacity of ~50%. Bovine serum albumin (BSA) was then adsorbed onto the CT surface to afford a complete albumin corona without obvious denaturation (CTB). CTB showed uniform particle size distribution and sufficient stability in vitro and in vivo. Besides clathrin-mediated and macropinocytosis pathways, CTB was actively internalized through megalin receptor-mediated endocytosis in HK-2 cells. Per biodistribution studies, CTB demonstrates enhanced renal tubule-specific distribution and targetability in mice compared to CT without albumin corona. Furthermore, pharmacodynamic studies in vivo further support that CTB effectively alleviated ischemia-reperfusion induced injuries without obvious systemic side effects in AKI mice models.
肾小管上皮细胞（RTEC）是治疗急性肾损伤（AKI）的关键靶细胞。尽管通过全身给予配体修饰的纳米颗粒（NPs）已经有多种针对 RTEC 的策略，但 NPs 与血浆蛋白之间的非特异性相互作用大大降低了 NPs 的靶向效率和稳定性。在此，将雷公藤红素（CLT）包封在 D-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS）中，形成具有约 50%高载药量的 CLT 负载纳米复合物核心（CT）。然后，牛血清白蛋白（BSA）吸附到 CT 表面，形成完整的白蛋白外壳而没有明显变性（CTB）。CTB 在体外和体内均表现出均匀的粒径分布和足够的稳定性。除了网格蛋白介导的内吞作用和巨胞饮作用途径外，CTB 还可以通过巨胞饮受体介导的内吞作用在 HK-2 细胞中被主动内化。通过生物分布研究，与没有白蛋白外壳的 CT 相比，CTB 在小鼠中表现出增强的肾小管特异性分布和靶向性。此外，体内药效学研究进一步支持 CTB 在 AKI 小鼠模型中有效缓解缺血再灌注引起的损伤，而没有明显的全身副作用。
