RNAi-based Therapeutics Targeting Survivin and PLK1 for Treatment of Bladder Cancer
RNAi-based Therapeutics Targeting Survivin and PLK1 for Treatment of Bladder Cancer
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DOI：
10.1038/mt.2011.21
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发表时间：
2011-05-01
影响因子：
12.4
通讯作者：
Polisky, Barry
中科院分区：
文献类型：
--
作者：
Seth, Shaguna;Matsui, Yoshiyuki;Polisky, Barry
利用RNA干扰（RNAi）沉默异常基因表达是癌症治疗中的新兴方法。通过RNAi选择性抑制过表达的基因需要高度有效的靶特异性短干扰RNA（siRNA）和安全有效的递送系统。我们已经开发了siRNA构建体（USiRNA），其含有靶向生存素和polo样激酶-1（PLK 1）基因的解锁核碱基类似物（UNA）。将UsiRNA包封在含有去甲精氨酸头基、胆固醇半琥珀酸酯（CHEMS）、胆固醇和1，2-二肉豆蔻酰-磷脂酰乙醇胺-聚乙二醇2000（DMPE-PEG 2000）的基于二烷基化氨基酸的脂质体（DiLA（2））中。在原位膀胱癌小鼠模型中，以1.0和0.5 mg/kg的DiLA（2）脂质体中的生存素或PLK 1 UsiRNA进行膀胱内治疗，分别导致生存素或PLK 1 mRNA的90%和70%抑制。这与肿瘤体积的剂量依赖性减少相关，持续3周。在研究期间，在膀胱肿瘤中检测到特异性切割产物，证实Survivin和PLK 1 mRNA的沉默是RNA诱导的沉默复合物介导的。该报告表明，膀胱内滴注生存素或PLK 1 UsiRNA可以作为治疗膀胱癌的潜在治疗方式。
Harnessing RNA interference (RNAi) to silence aberrant gene expression is an emerging approach in cancer therapy. Selective inhibition of an overexpressed gene via RNAi requires a highly efficacious, target-specific short interfering RNA (siRNA) and a safe and efficient delivery system. We have developed siRNA constructs (UsiRNA) that contain unlocked nucleobase analogs (UNA) targeting survivin and polo-like kinase-1 (PLK1) genes. UsiRNAs were encapsulated into dialkylated amino acid-based liposomes (DiLA(2)) containing a nor-arginine head group, cholesteryl hemisuccinate (CHEMS), cholesterol and 1, 2-dimyristoyl-phosphatidylethanolamine-polyethyleneglycol 2000 (DMPE-PEG2000). In an orthotopic bladder cancer mouse model, intravesical treatment with survivin or PLK1 UsiRNA in DiLA(2) liposomes at 1.0 and 0.5 mg/kg resulted in 90% and 70% inhibition of survivin or PLK1 mRNA, respectively. This correlated with a dose-dependent decrease in tumor volumes which was sustained over a 3-week period. Silencing of survivin and PLK1 mRNA was confirmed to be RNA-induced silencing complex mediated as specific cleavage products were detected in bladder tumors over the duration of the study. This report suggests that intravesical instillation of survivin or PLK1 UsiRNA can serve as a potential therapeutic modality for treatment of bladder cancer.