A tumor-targeting cRGD-EGFR siRNA conjugate and its anti-tumor effect on glioblastoma in vitro and in vivo.
A tumor-targeting cRGD-EGFR siRNA conjugate and its anti-tumor effect on glioblastoma in vitro and in vivo.
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肿瘤靶向 cRGD-EGFR siRNA 缀合物及其对胶质母细胞瘤的体外和体内抗肿瘤作用
DOI：
10.1080/10717544.2016.1267821
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发表时间：
2017-11
期刊：
影响因子：
6
通讯作者：
Ji A
中科院分区：
文献类型：
--
作者：
He S;Cen B;Liao L;Wang Z;Qin Y;Wu Z;Liao W;Zhang Z;Ji A
摘要表皮生长因子受体（EGFR）是一个重要的抗肿瘤靶点。因此，开发能够靶向肿瘤细胞内部并特异性沉默EGFR表达的新型分子靶向抗肿瘤药物具有重要的应用价值。在这项工作中，合成并检测了一种有前途的抗肿瘤缀合物，其包含甲氧基修饰的EGFR siRNA和环状精氨酸-甘氨酸-天冬氨酸（cRGD）肽，其选择性地结合αvβ3整联蛋白。为了制备cRGD-EGFR siRNA（cRGD-siEGFR），使用巯基-马来酰亚胺接头将cRGD共价缀合至siRNA有义链的5′-末端。使用αvβ3阳性U87 MG细胞系测试cRGD-siEGFR的体外细胞摄取和细胞毒性。在裸鼠肿瘤模型中，通过重复静脉内给予cRGD-siEGFR（间隔48小时内7次），研究了体内生物分布、抗肿瘤活性、免疫原性和毒性。体外数据分析表明，cRGD-siEGFR有效沉默EGFR表达，具有较高的肿瘤靶向能力。cRGD-siEGFR对荷瘤裸鼠的肿瘤生长有明显抑制作用，肿瘤组织EGFR表达明显降低，EGFR mRNA和蛋白表达下调。此外，血清生化和病理切片评估未表明cRGD-siEGFR在体内的任何严重毒性。cRGD-siEGFR具有靶向性强、体内外毒性低、抗肿瘤效果显著等特点，是一种很有前景的候选靶向治疗药物。
Abstract The epidermal growth factor receptor (EGFR) is an important anti-tumor target. The development of novel molecular-targeted anti-tumor drugs that can target the interior of tumor cells and specifically silence EGFR expression is valuable and promising. In this work, a promising anti-tumor conjugate comprising methoxy-modified EGFR siRNA and cyclic arginine-glycine-aspartic acid (cRGD) peptides, which selectively bind to αvβ3 integrins, was synthesized and examined. To prepare cRGD-EGFR siRNA (cRGD-siEGFR), cRGD was covalently conjugated to the 5′-end of an siRNA sense strand using a thiol-maleimide linker. The cellular uptake and cytotoxicity of cRGD-siEGFR in vitro were tested using an αvβ3-positive U87MG cell line. In vivo bio-distribution, anti-tumor activity, immunogenicity and toxicity were investigated in a nude mouse tumor model through repeated i.v. administration of cRGD-siEGFR (7 times over a 48 h interval). Analyses of in vitro data showed that cRGD-siEGFR silenced EGFR expression effectively, with high tumor targeting ability. Administration of cRGD-siEGFR to tumor-bearing nude mice led to significant inhibition of tumor growth, obvious reduction of EGFR expression and down-regulation of EGFR mRNA and protein in tumor tissue. Furthermore, serum biochemistry and pathological section evaluation did not indicate any serious toxicity of cRGD-siEGFR in vivo. cRGD-siEGFR is likely a promising candidate with high targeting ability, substantial anti-tumor effects and low toxicity in vitro and in vivo.
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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：
14.9
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
通讯作者：
Ji A
影响因子：
8
作者：
Liu L;Liu X;Xu Q;Wu P;Zuo X;Zhang J;Deng H;Wu Z;Ji A
通讯作者：
Ji A
用于基因沉默治疗药物全身递送的高容量纳米多孔硅载体
影响因子：
17.1
作者：
Shen, Jianliang;Xu, Rong;Mai, Junhua;Kim, Han-Cheon;Guo, Xiaojing;Qin, Guoting;Yang, Yong;Wolfram, Joy;Mu, Chaofeng;Xia, Xiaojun;Gu, Jianhua;Liu, Xuewu;Mao, Zong-Wan;Ferrari, Mauro;Shen, Haifa
通讯作者：
Shen, Haifa
DOI：
10.1016/j.nano.2014.08.004
发表时间：
2015-02-01
影响因子：
5.4
作者：
Knudsen, Kristina Bram;Northeved, Helle;Roursgaard, Martin
通讯作者：
Roursgaard, Martin