In Vitro and In Vivo gene delivery mediated by Lactosylated Dendrimer/α-Cyclodextrin Conjugates (G2) into Hepatocytes
In Vitro and In Vivo gene delivery mediated by Lactosylated Dendrimer/α-Cyclodextrin Conjugates (G2) into Hepatocytes
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DOI：
10.1016/j.jconrel.2010.05.030
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发表时间：
2010-08-17
影响因子：
10.8
通讯作者：
Uekama, Kaneto
中科院分区：
文献类型：
--
作者：
Arima, Hidetoshi;Yamashita, Shogo;Uekama, Kaneto
本研究的目的是评估聚酰胺胺（PAMAM）星突树突状大分子（第2代，G2）与含有乳糖（lac - α - cde）的a-环糊精（α - cde (G2)）结合的体外和体内基因传递效率，并将乳糖部分（DSL）的不同程度取代作为一种新的肝细胞选择性载体在肝细胞中传递。在HepG2细胞中，lac - α - cde （DSL 2.6）的基因转移活性远高于树突状分子、α - cde、lac - α - cde （DSL 1.2、4.6、6.2和10.2）和乳糖化树突状分子（lac -树突状分子，DSL 2.4），其基因转移活性依赖于细胞表面asialal糖蛋白受体（ASGP-R）的表达，反映了质粒DNA （pDNA）复合物的细胞关联。与lac - α - cde （DSL 2.6）配合的pDNA的理化性质与α - cde基本相当。lac - α - cde （DSL 2.6）在HepG2细胞中可忽略不计的细胞毒性，其电荷比高达150。lac - α - cde （DSL 2.6）在小鼠肝细胞间的基因转移活性高于jetPEI (TM)-肝细胞，且静脉给药12 h后血液化学值变化小得多。这些结果提示lac - α - cde （DSL 2.6）作为一种向肝细胞传递基因的非病毒载体的潜在用途。(C) 2010 Elsevier B.V.版权所有
The purpose of this study is to evaluate in vitro and in vivo gene delivery efficiency of polyamidoamine (PAMAM) starburst dendrimer (generation 2, G2) conjugates with a-cyclodextrin (alpha-CDE (G2)) bearing lactose (Lac-alpha-CDE) with various degrees of substitution of the lactose moiety (DSL) as a novel hepatocyte-selective carrier in hepatocytes. Lac-alpha-CDE (DSL 2.6) was found to have much higher gene transfer activity than dendrimer, alpha-CDE, Lac-alpha-CDE (DSL 1.2, 4.6, 6.2 and 10.2) and lactosylated dendrimer (Lac-dendrimer, DSL 2.4) in HepG2 cells, which are dependent on the expression of cell-surface asialoglycoprotein receptor (ASGP-R), reflecting the cellular association of the plasmid DNA (pDNA) complexes. The physicochemical properties of pDNA complex with Lac-alpha-CDE (DSL 2.6) were almost comparable to that with alpha-CDE. Lac-alpha-CDE (DSL 2.6) provided negligible cytotoxicity up to a charge ratio of 150 in HepG2 cells. Lac-alpha-CDE (DSL 2.6) provided gene transfer activity higher than jetPEI (TM)-Hepatocyte to hepatocytes with much less changes of blood chemistry values 12 h after intravenous administration in mice. These results suggest the potential use of Lac-alpha-CDE (DSL 2.6) as a non-viral vector for gene delivery toward hepatocytes. (C) 2010 Elsevier B.V. All rights reserved.