Dong Lei, Zuo Longsheng, Xia Suhua, Gao Shuying, Zhang Chenyu, Chen Jiangning, Zhang Junfeng
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biochemistry, Nanjing University, Nanjing, China.
J Gene Med. 2009 Mar;11(3):229-39. doi: 10.1002/jgm.1293.
Fulminant liver failure can cause extreme mortality due to the lack of effective and targeting therapeutics for the disease. Novel therapeutics using antisense technology require an efficient and safe delivery system with Kupffer cell targeting ability.
We explored the capacity of galactosylated low molecular weight chitosan (GLC) to efficiently mediate the antisense oligonucleotide (ASO) TJU-2755 into Kupffer cells, enhance the effect of the oligonucleotides on the suppression of tumor necrosis factor (TNF)-alpha and prolong the active time of the antisense drug in vivo. The protective and therapeutic effect of ASO/GLC in the animal model of D-galactosamine/lipopolysaccharide-induced fulminant hepatitis was tested.
ASOs delivered by GLC were concentrated in Kupffer cells and more potent in reducing the expression of TNF-alpha mRNA, as well as reducing serum TNF-alpha levels. Furthermore, the ASO/GLC complex successfully rescued animals from fulminant hepatitis and mortality. Compared to naked ASO, the complex notably reduced the dose administrated in animals and prolonged its effectiveness. A single dose of 5 mg ASO per kg body weight achieved a satisfactory effect after 5 days, and 20 mg ASO per kg body weight preserved 70% of the effect after more than 2 weeks. Its efficacy was affirmed through both pretreatment and therapeutic use after liver damage had begun.
Inhibiting TNF-alpha expression in the liver by this strategy represents a novel therapeutic approach that may be valuable for the treatment of some inflammation-related liver diseases.
由于缺乏针对暴发性肝衰竭的有效且靶向性治疗方法，其死亡率极高。使用反义技术的新型治疗方法需要一种具有库普弗细胞靶向能力的高效且安全的递送系统。
我们探究了半乳糖基化低分子量壳聚糖（GLC）有效介导反义寡核苷酸（ASO）TJU - 2755进入库普弗细胞的能力，增强寡核苷酸对肿瘤坏死因子（TNF）-α的抑制作用，并延长反义药物在体内的活性时间。测试了ASO/GLC在D - 半乳糖胺/脂多糖诱导的暴发性肝炎动物模型中的保护和治疗效果。
由GLC递送的ASO集中在库普弗细胞中，在降低TNF -α mRNA表达以及降低血清TNF -α水平方面更有效。此外，ASO/GLC复合物成功使动物从暴发性肝炎和死亡中获救。与裸ASO相比，该复合物显著降低了动物给药剂量并延长了其有效性。每千克体重单次给予5毫克ASO在5天后取得了满意效果，每千克体重20毫克ASO在超过2周后仍保留70%的效果。在肝损伤开始后的预处理和治疗应用中均证实了其疗效。
通过该策略抑制肝脏中TNF -α的表达代表了一种新型治疗方法，可能对某些炎症相关肝病的治疗具有重要价值。
