Tumor-targeted in vivo gene silencing via systemic delivery of cRGD-conjugated siRNA.
Tumor-targeted in vivo gene silencing via systemic delivery of cRGD-conjugated siRNA.
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DOI：
10.1093/nar/gku831
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发表时间：
2014-10
影响因子：
14.9
通讯作者：
Ji A
中科院分区：
文献类型：
--
作者：
Liu X;Wang W;Samarsky D;Liu L;Xu Q;Zhang W;Zhu G;Wu P;Zuo X;Deng H;Zhang J;Wu Z;Chen X;Zhao L;Qiu Z;Zhang Z;Zeng Q;Yang W;Zhang B;Ji A
RNAi技术在关键治疗模式中占据重要地位，数十个基于siRNA的项目进入并成功进入药物开发的临床阶段。为了进一步探索RNAi技术作为治疗方法的潜力，我们通过共价缀合的环（Arg-Gly-Asp-d-Phe-LyS[PEG-MAL]）（cRGD）肽（已知可结合αvβ3整联蛋白受体）设计并测试了特异性靶向肿瘤的VEGFR 2 siRNA分子。cRGD-siRNA被证明可以特异性进入培养的αvβ3阳性人细胞（HUVEC）并沉默靶基因。用VEGFR 2 cRGD-siRNA显微注射斑马鱼囊胚导致血管生长的特异性抑制。在荷瘤小鼠中，静脉注射cRGD-siRNA分子不会产生先天免疫应答，并生物分布到肿瘤组织中。两种不同VEGFR 2 cRGD-siRNA的连续全身递送导致肿瘤中相应mRNA（55和45%）和蛋白质（65和45%）的下调，以及肿瘤体积的总体减小（90和70%）。这些发现证明了cRGD-siRNA分子作为抗肿瘤疗法的强大潜力。
RNAi technology is taking strong position among the key therapeutic modalities, with dozens of siRNA-based programs entering and successfully progressing through clinical stages of drug development. To further explore potentials of RNAi technology as therapeutics, we engineered and tested VEGFR2 siRNA molecules specifically targeted to tumors through covalently conjugated cyclo(Arg-Gly-Asp-d-Phe-Lys[PEG-MAL]) (cRGD) peptide, known to bind αvβ3 integrin receptors. cRGD-siRNAs were demonstrated to specifically enter and silence targeted genes in cultured αvβ3 positive human cells (HUVEC). Microinjection of zebrafish blastocysts with VEGFR2 cRGD-siRNA resulted in specific inhibition of blood vessel growth. In tumor-bearing mice, intravenously injected cRGD-siRNA molecules generated no innate immune response and bio-distributed to tumor tissues. Continuous systemic delivery of two different VEGFR2 cRGD-siRNAs resulted in down-regulation of corresponding mRNA (55 and 45%) and protein (65 and 45%) in tumors, as well as in overall reduction of tumor volume (90 and 70%). These findings demonstrate strong potential of cRGD-siRNA molecules as anti-tumor therapy.
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影响因子：
46.9
作者：
Alvarez-Erviti, Lydia;Seow, Yiqi;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
46.9
作者：
Dassie, Justin P.;Liu, Xiu-ying;Thomas, Gregory S.;Whitaker, Ryan M.;Thiel, Kristina W.;Stockdale, Katie R.;Meyerholz, David K.;McCaffrey, Anton P.;McNamara, James O., II;Giangrande, Paloma H.
通讯作者：
Giangrande, Paloma H.
影响因子：
4.7
作者：
Alam, Md Rowshon;Ming, Xin;Fisher, Michael;Lackey, Jeremy G.;Rajeev, Kallanthottathil G.;Manoharan, Muthiah;Juliano, Rudy L.
通讯作者：
Juliano, Rudy L.
影响因子：
12.4
作者：
Nishina, Kazutaka;Unno, Toshinori;Yokota, Takanori
通讯作者：
Yokota, Takanori
影响因子：
4.8
作者：
Chen, XY;Sievers, E;Conti, PS
通讯作者：
Conti, PS