Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice

被引：331

作者：

Judge, Adam D. ^{[1
]}

Robbins, Marjorie ^{[1
]}

Tavakoli, Iran ^{[1
]}

Levi, Jasna ^{[1
]}

Hu, Lina ^{[1
]}

Fronda, Anna ^{[1
]}

Ambegia, Ellen ^{[1
]}

McClintock, Kevin ^{[1
]}

MacLachlan, Ian ^{[1
]}

机构：

[1] Tekmira Pharmaceut Corp, Burnaby, BC, Canada

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2009年 / 119卷 / 03期

基金：

加拿大自然科学与工程研究理事会;

关键词：

MOUSE VASCULAR ENDOTHELIUM; INNATE IMMUNE-RESPONSE; MITOTIC KINESIN KSP; POLO-LIKE KINASE-1; IN-VIVO; MAMMALIAN-CELLS; NONHUMAN-PRIMATES; PASSENGER-STRAND; INTERFERON-ALPHA; SYNTHETIC SIRNA;

D O I：

10.1172/JCI37515

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

100103 [病原生物学]; 100218 [急诊医学];

摘要：

siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in both hepatic and subcutaneous tumor models. This was correlated with target gene silencing following a single intravenous administration that was sufficient to cause extensive mitotic disruption and tumor cell apoptosis. Our siRNA formulations induced no measurable immune response, minimizing the potential for nonspecific effects. Additionally, RNAi-specific mRNA cleavage products were found in tumor cells, and their presence correlated with the duration of target mRNA silencing. Histological biomarkers confirmed that RNAi-mediated gene silencing effectively inhibited the target's biological activity. This report supports an RNAi-mediated mechanism of action for siRNA antitumor effects, suggesting a new methodology for targeting other key genes in cancer development with siRNA-based therapeutics.

引用

页码：661 / 673

页数：13

共 64 条

[1]

Stabilized plasmid-lipid particles containing PEG-diacylglycerols exhibit extended circulation lifetimes and tumor selective gene expression [J].