Improvement of gene delivery mediated by mannosylated dendrimer/α-cyclodextrin conjugates
Improvement of gene delivery mediated by mannosylated dendrimer/α-cyclodextrin conjugates
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DOI：
10.1016/j.jconrel.2005.02.016
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发表时间：
2005-05-18
影响因子：
10.8
通讯作者：
Uekama, K
中科院分区：
文献类型：
--
作者：
Wada, K;Arima, H;Uekama, K
本研究的目的是评价含有甘露糖的聚酰胺胺(PAMAM)星状突起树状大分子(第2代，G2代)与含甘露糖的α-环糊精(α-CDE偶联物(G2))的结合物(Man-α-CDE偶联物)作为一种新型的非病毒载体在多种细胞中的体内外基因传递效率。在不同的细胞中，MAN-α-CDE结合物(DSM 3.3和4.9)比树状大分子、α-CDE结合物和MAN-α-CDE结合物(DSM 1.1和8.3)具有更高的基因转移活性，这与细胞表面甘露糖受体的表达无关。PDNA络合物与树状大分子、α-CDE偶联物和Man-a-CDE偶联物(DSM 3.3)的细胞结合作用和它们的细胞毒作用只有很小的差别。表面等离子体共振研究表明，人-α-CDE偶联物与刀豆蛋白A的结合活性不是很强。更多的甘露糖部分与α-CDE偶联物的结合为基因转移提供了不利的PDNA复合体的物理化学性质，例如，与PDNA的相互作用低，PDNA的酶稳定性低，以及PDNA缺乏紧密性。小鼠静脉注射12h后，MAN-α-CDE结合物(DSM 3.3)的基因转移活性高于树枝状大分子和α-CDE结合物。这些结果提示了Man-α-CDE结合物(DSM 3.3)作为非病毒载体的潜在用途。(C)2005爱思唯尔B.V.保留所有权利。
The purpose of this study is to evaluate in vitro and in vivo gene delivery efficiency of polyamidoamine (PAMAM) starburst dendrimer (generation 2, G2) conjugate with alpha-cyclodextrin (alpha-CDE conjugate (G2)) bearing mannose (Man-alpha-CDE conjugates) with the various degrees of substitution of the mannose moiety (DSM) as a novel non-viral vector in a variety of cells. Man-alpha-CDE conjugates (DSM 3.3 and 4.9) were found to have much higher gene transfer activity than dendrimer, a-CDE conjugate and Man-alpha-CDE conjugates (DSM 1.1 and 8.3) in various cells, which are independent of the expression of cell surface mannose receptors. Cellular association of pDNA complexes with dendrimer, alpha-CDE conjugate and Man-a-CDE conjugate (DSM 3.3) and their cytotoxic effects differed only very slightly. Surface plasmon resonance study demonstrated that the specific binding activity of Man-alpha-CDE conjugates to concanavalin A was not very strong. Much more conjugation of the mannose moiety to alpha-CDE conjugates provided unfavorable physicochemical properties of pDNA complexes for gene transfer, e.g. the low interaction with pDNA, the low enzymatic stability of pDNA and the lack of pDNA compaction. Man-alpha-CDE conjugate (DSM 3.3) provided gene transfer activity higher than dendrimer and alpha-CDE conjugate in kidney 12 h after intravenous injection in mice. These results suggest the potential use of Man-alpha-CDE conjugate (DSM 3.3) as a non-viral vector. (c) 2005 Elsevier B.V All rights reserved.