Systemic delivery of siRNA nanoparticles targeting RRM2 suppresses head and neck tumor growth

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• 作者：Mohammad Aminur Rahman^a ; A.R.M. Ruhul Amin^a ; Xu Wang^a ; Jonathan E. Zuckerman^b ; Chung Hang J. Choi^b ; Bingsen Zhou^c ; Dongsheng Wang^a ; Sreenivas Nannapaneni^a ; Lydia Koenig^a ; Zhengjia Chen^d ; Zhuo (Georgia) Chen^a ; Yun Yen^c ; Mark E. Davis^b ; Dong M. Shin^a ; ^{dmshin@emory.edu}
• 关键词：SiRNA delivery ; Targeted nanoparticle ; RNA interference ; RRM2 ; TfR ; Tumor growth
• 刊名：Journal of Controlled Release
• 出版年：2012
• 期刊代码：25_01683659
• 类别：pha
• 出版时间：10 May, 2012
• 卷：159
• 期：3
• 页码：384-392
• 文件大小：1338 K

摘要

Systemic delivery of siRNA to solid tumors remains challenging. In this study, we investigated the systemic delivery of a siRNA nanoparticle targeting ribonucleotide reductase subunit M2 (RRM2), and evaluated its intratumoral kinetics, efficacy and mechanism of action. Knockdown of RRM2 by an RNAi mechanism strongly inhibited cell growth in head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cell lines. In a mouse xenograft model of HNSCC, a single intravenous injection led to the accumulation of intact nanoparticles in the tumor that disassembled over a period of at least 3 days, leading to target gene knockdown lasting at least 10 days. A four-dose schedule of siRNA nanoparticle delivering RRM2 siRNA targeted to HNSCC tumors significantly reduced tumor progression by suppressing cell proliferation and inducing apoptosis. These results show promise for the use of RRM2 siRNA-based therapy for HNSCC and possibly NSCLC.