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Design and Evaluation of dendrimer/cyclodextrin conjugates as a novel siRNA carrier

树枝状聚合物/环糊精缀合物作为新型 siRNA 载体的设计和评估

基本信息

批准号：
16590114
负责人：
ARIMA Hidetoshi
金额：
$ 2.3万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590114/
关键词：
siRNA cyclodextrin dendrimer conjugate carrier delivery multifunctionalization RNAi効果 Lipofectamine 2000

项目摘要

RNA interference (RNAi) is the mechanism of gene silencing-mediated messenger RNA degradation by small interference RNA (siRNA), which becomes a powerful tool for genetic analysis and novel gene therapy. However, one of the major obstacles for siRNA delivery is the difficulty to cross the biological membrane due to its hydrophilicity and high molecular weight. We evaluated the potential use of the starburst polyamidoamine dendrimer (generation 3) conjugate with α-cyclodextrin having an average degree of substitution of 2.4 (α-CDE conjugate) as a siRNA carrier for RNAi. The ternary complex composed of pGL2 control vector (pDNA)/pGL2 siRNA/α-CDE conjugate showed higher pGL2 siRNA sequence-specific gene silencing effects without off-target effects than those of commercial transfection reagents such as Lipofectamine^<TM>2000 (LP), TransFast^<TM> (TF) and Lipofectin^<TM> (LF). In the binary complex (siRNA/carrier) system, the similar inhibitory effects of α-CDE conjugate were observed without cytotoxicity. These superior RNAi effects of α-CDE conjugate to the other commercial transfection reagents could be attributed to stable complex formation and cytoplasmic distribution of siRNA after transfection. These results suggest that α-CDE conjugate has the potential to be a novel carrier for siRNA.

RNA干扰（RNA interference，RNAi）是通过小干扰RNA（small interference RNA，siRNA）介导的信使RNA（messenger RNA）降解机制，成为基因分析和新型基因治疗的有力工具。然而，siRNA递送的主要障碍之一是由于其亲水性和高分子量而难以穿过生物膜。我们评估了具有平均取代度为2.4的α-环糊精的星状聚酰胺胺树状聚合物（第3代）缀合物（α-CDE缀合物）作为RNAi的siRNA载体的潜在用途。pGL 2 siRNA/α-CDE三元复合物的序列特异性基因沉默效果明显优于Lipofectamine^<TM>2000（LP）、TransFast^<TM>（TF）和Lipofectin^<TM>（LF）。在siRNA/载体二元复合物体系中，α-CDE偶联物也有类似的抑制作用，无细胞毒性。α-CDE偶联物的这些上级RNAi效果优于其他商业转染试剂，这可能归因于转染后siRNA稳定的复合物形成和胞质分布。结果表明，α-CDE偶联物有望成为siRNA的新型载体。