A polyethylenimine-linoleic acid conjugate for antisense oligonucleotide delivery.
A polyethylenimine-linoleic acid conjugate for antisense oligonucleotide delivery.
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DOI：
10.1155/2013/710502
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发表时间：
2013
影响因子：
--
通讯作者：
Lee RJ
中科院分区：
文献类型：
--
作者：
Xie J;Teng L;Yang Z;Zhou C;Liu Y;Yung BC;Lee RJ
合成了一种新型的反义寡核苷酸（阿索）载体，聚乙烯亚胺共轭亚油酸（PEI-LA），并评估了LOR-2501对肿瘤细胞的递送。LOR-2501是一种靶向核糖核苷酸还原酶R1亚基（RRM 1）的阿索。本研究以聚乙烯亚胺（PEI）（分子量约800）为原料，与亚油酰氯反应合成了聚乙烯亚胺-亚油酸（PEI-LA）。凝胶阻滞测定显示在N/P比大于8时PEI-LA和LOR-2501之间完全络合。在试验剂量水平下，这些复合物未观察到显著的细胞毒性。有趣的是，在N/P比>6时，PEI-LA/LOR-2501的细胞摄取水平是相同N/P比的PEI/LOR-2501复合物的两倍。PEI-LA/LOR-2501在mRNA和蛋白水平分别诱导RRM 1下调64%和70%。PEI-LA/LOR-2501复合物在N/P比为10时显示出最高的转染活性。最后，使用途径特异性抑制剂，网格蛋白介导的内吞作用被证明是这些复合物的细胞内化的主要机制。总之，PEI-LA是一种很有前途的药物，用于递送ASO，值得进一步研究。
A novel antisense oligonucleotide (ASO) carrier, polyethylenimine conjugated to linoleic acid (PEI-LA), was synthesized and evaluated for delivery of LOR-2501 to tumor cells. LOR-2501 is an ASO targeting ribonucleotide reductase R1 subunit (RRM1). In this study, PEI-LA was synthesized by reacting PEI (Mw ~ 800) with linoleoyl chloride. Gel retardation assay showed complete complexation between PEI-LA and LOR-2501 at N/P ratio above 8. No significant cytotoxicity was observed with these complexes at the tested dosage levels. Interestingly, at N/P ratio of >6, levels of cellular uptake of PEI-LA/LOR-2501 were double that of PEI/LOR-2501 complexes of the same N/P ratio. PEI-LA/LOR-2501 induced downregulation of 64% and 70% of RRM1 at mRNA and protein levels, respectively. The highest transfection activity was shown by PEI-LA/LOR-2501 complexes at N/P ratio of 10. Finally, using pathway specific inhibitors, clathrin-mediated endocytosis was shown to be the principle mechanism of cellular internalization of these complexes. In conclusion, PEI-LA is a promising agent for the delivery of ASOs and warrants further investigation.
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影响因子：
5.1
作者：
Kircheis, R;Wightman, L;Wagner, E
通讯作者：
Wagner, E
影响因子：
3.5
作者：
Boeckle, S;von Gersdorff, K;Ogris, M
通讯作者：
Ogris, M
影响因子：
2.9
作者：
Braasch, DA;Corey, DR
通讯作者：
Corey, DR
影响因子：
4.7
作者：
Kim, Tae-il;Baek, Jung-un;Park, Jong-sang
通讯作者：
Park, Jong-sang
交联的小聚乙基亚胺：虽然仍然无毒，但在体外和体内有效地递送DNA。
影响因子：
3.7
作者：
Thomas M;Ge Q;Lu JJ;Chen J;Klibanov AM
通讯作者：
Klibanov AM