Zhang Zhirong, Zheng Qiang, Han Jing, Gao Guangping, Liu Jie, Gong Tao, Gu Zhongwei, Huang Yuan, Sun Xun, He Qin
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, PR China.
Biomaterials. 2009 Mar;30(7):1372-81. doi: 10.1016/j.biomaterials.2008.11.035. Epub 2008 Dec 18.
We have synthesized a renal-specific drug carrier, 14-succinyl triptolide-lysozyme (TPS-LZM) conjugate for targeted delivery of TP to the PTECs. TPS-LZM could be taken up by HK-2 cells, free TP would be degraded and released, mainly from basolateral side of the cells. Compared with TP, the overall targeting efficiency (TE) of TPS-LZM was significantly enhanced from 11.74% to 95.54% and its MRT was moderately prolonged from 3.08h to 4.10h. At very low concentration, TPS-LZM could significantly reverse the disease progression in renal ischemia-reperfusion (I/R) injury animal models, while the mixture of free TP and LZM was ineffective. Further, TPS-LZM conjugate presented much lower hepatotoxicity (0.78 folds lower than TP) and no adverse effect on the immune (1.13 folds higher than TP) and genital system. Thus, TPS-LZM represents a very effective drug candidate for specific treatment of immunological renal diseases with low adverse side effect.
我们合成了一种肾特异性药物载体，即14-琥珀酰雷公藤甲素-溶菌酶（TPS-LZM）偶联物，用于将雷公藤甲素（TP）靶向递送至近端肾小管上皮细胞（PTECs）。TPS-LZM可被HK-2细胞摄取，游离的TP会被降解并释放，主要从细胞的基底外侧释放。与TP相比，TPS-LZM的整体靶向效率（TE）从11.74%显著提高到95.54%，其平均滞留时间（MRT）从3.08小时适度延长至4.10小时。在极低浓度下，TPS-LZM可显著逆转肾缺血再灌注（I/R）损伤动物模型中的疾病进展，而游离TP和溶菌酶的混合物则无效。此外，TPS-LZM偶联物的肝毒性低得多（比TP低0.78倍），对免疫（比TP高1.13倍）和生殖系统无不良影响。因此，TPS-LZM是一种非常有效的药物候选物，可用于特异性治疗免疫性肾脏疾病，且副作用低。
