Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application
Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application
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DOI：
10.1038/sj.gt.3301351
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发表时间：
2001-01-01
期刊：
影响因子：
5.1
通讯作者：
Wagner, E
中科院分区：
文献类型：
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作者：
Kircheis, R;Wightman, L;Wagner, E
系统应用带正电荷的聚阳离子/DNA复合物已显示导致肺中的主要基因表达。将基因表达靶向其他位点，例如远处肿瘤，受到非特异性相互作用的阻碍，这主要是由于转染复合物的正表面电荷。在本研究中，我们表明，PN（25 kDa的分支或22 kDa的线性）/DNA复合物的正表面电荷可以有效地屏蔽共价结合转铁蛋白在足够高的密度在复杂的，导致在非特异性相互作用，如与红细胞，并减少在肺中的基因表达显着减少。通过尾静脉将转铁蛋白屏蔽的PEI/DNA复合物全身应用于皮下生长Neuro 2a肿瘤的A/J小鼠中，导致与包括肺在内的主要器官相比，远处肿瘤中的荧光素酶报告基因表达优先（高100至500倍）。肿瘤靶向也通过肿瘤细胞中的DNA摄取和β-半乳糖苷酶基因表达来证明。评估全身应用后的DNA分布，在肝脏和肿瘤中发现了显著量的DNA。然而，在肝脏中，DNA主要被枯否细胞吸收并降解，而没有显著的转基因表达。在肿瘤中，DNA主要与肿瘤细胞相关，并且经常在类似原始血管的结构附近发现。
Systemic application of positively charged polycation/DNA complexes has been shown to result in predominant gene expression in the lungs. Targeting gene expression to other sites, eg distant tumors, is hampered by nonspecific interactions largely due to the positive surface charge of transfection complexes. In the present study we show that the positive surface charge of PN (25kDa branched or 22kDa linear)/DNA complexes can be efficiently shielded by covalently incorporating transferrin at sufficiently high densities in the complex, resulting in a dramatic decrease in nonspecific interactions, eg with erythrocytes, and decreased gene expression in the lung. Systemic application of transferrin-shielded PEI/DNA complexes into A/J mice bearing subcutaneously growing Neuro2a tumors via the tail vein resulted in preferential (100- to 500-fold higher) luciferase reporter gene expression in distant tumors as compared with the major organs including the lungs. Tumor targeting is also demonstrated by DNA uptake and beta -galactosidase gene expression in tumor cells. Assessing DNA distribution following systemic application significant amounts of DNA were found in the liver and tumor. However, in the liver, DNA was mainly taken up by Kupffer cells and degraded without significant transgene expression. In the tumor, DNA was associated mainly with tumor cells and frequently found near structures which resemble primitive blood vessels.