Manipulation of local disposition and gene expression characteristics of plasmid DNA following intramuscular administration by complexation with cationic macromolecule
Manipulation of local disposition and gene expression characteristics of plasmid DNA following intramuscular administration by complexation with cationic macromolecule
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DOI：
10.1016/j.ijpharm.2004.12.011
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发表时间：
2005-04-11
影响因子：
5.8
通讯作者：
Takakura, Y
中科院分区：
文献类型：
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作者：
Kawase, A;Kobayashi, N;Takakura, Y
为了调节DNA疫苗的免疫反应，局部施用后控制质粒DNA（pDNA）的处置和基因表达非常重要。我们选择甲基化牛血清白蛋白（mBSA）这种阳离子高分子作为pDNA的载体。我们研究了 pDNA 与 mBSA 的络合对肌肉注射后小鼠体内处置和基因表达的影响。带正电的 mBSA/pDNA 复合物从注射部位的消除被延迟，并且淋巴结的积累增加。随着 mBSA/pDNA 复合物的电荷比较高，基因表达水平降低。使用编码卵清蛋白(OVA)的pDNA、pCMV-OVA作为表达抗原的模型pDNA来评估抗原特异性免疫反应。然而，在用带正电荷的复合物 mBSA/pCMV-OVA (8:1)（重量比）免疫的小鼠中获得了显着水平的抗卵清蛋白 IgG 抗体的产生。使用 DC2.4 细胞（一种鼠树突状细胞系）进行的体外实验表明，络合可增加基因表达和细胞因子释放的水平。这些结果表明，免疫反应可能是通过络合来操纵的，这可能是由于 pDNA 的处置和基因表达的改变所致。 (c) 2005 Elsevier B.V. 保留所有权利。
To modulate the immune responses of DNA vaccine, it is very important to control the disposition and gene expression of plasmid DNA (pDNA) after local administration. We chose methylated bovine serum albumin (mBSA), a cationic macromolecule, as a carrier of pDNA. We examined the effects of complexation of pDNA with mBSA on the disposition and gene expression in mice after intramuscular administration. The elimination from injection site was retarded and the accumulation to lymph nodes was increased at the positively charged mBSA/pDNA complexes. As the charge ratios of mBSA/pDNA complexes were higher, the levels of gene expression were reduced. Antigen specific immune responses were evaluated using pDNA encoding ovalbumin (OVA), pCMV-OVA, as a model antigen-expressing pDNA. However, significant levels of production of anti-ovalbumin IgG antibody were obtained in mice immunized with a positively charged complex, mBSA/pCMV-OVA (8:1) (weight ratio). In vitro experiments using DC2.4 cells, a murine dendritic cell line, demonstrated that the levels of gene expression and cytokine release were increased by complexation. These results suggest that the immune responses might be manipulated by complexation presumably due to the altered disposition and gene expression of pDNA. (c) 2005 Elsevier B.V. All rights reserved.