siRNA能夠阻斷細胞內(nèi)可能發(fā)生的有害活動,，如腫瘤細胞的生長。但是要成功地將siRNA傳送到特異性的細胞中而不對其它細胞產(chǎn)生不利影響還一直是個難題,。
美國愛荷華大學的研究人員通過修飾siRNA,，使得將這種siRNA注射到血液后，能夠特異性地影響靶細胞,，并且降低對其他細胞的副作用。這項研究是在患前列腺癌的模式生物上完成的,，或許有助于開發(fā)大量的針對癌癥或其他疾病的治療性的siRNA。這篇研究報告發(fā)表在8月23日的Nature Biotechnology雜志上,。
之前,，杜克大學Giangrande課題組的研究表明,，一種名為aptamer的化合物可與siRNA結(jié)合使用靶向某些基因。當將這種結(jié)合使用的分子直接注射到動物模型的腫瘤中,，發(fā)現(xiàn)它能夠終止腫瘤的生長過程。但是,，將其直接注射到人體腫瘤細胞中還存在一些問題,。
在最近的這項研究中，研究人員將這種前列腺癌特異性的aptamer的大小進行削減,，然后通過修飾siRNA以增強其活性,。然后將二者結(jié)合注射到血液中，發(fā)現(xiàn)可以抑制腫瘤的生長并且對正常組織沒有影響,。
課題組還表示,，因為多數(shù)siRNA在發(fā)揮功能之前可通過腎臟排出體外,，因此siRNA的需要量非常大。為了保持siRNA在機體內(nèi)存留時間更長,，課題組利用一種稱為“PEGlyation”的過程對siRNA進行修飾,。
雖然目前的這項研究集中在對前列腺癌的研究，但這項發(fā)現(xiàn)或許還能應(yīng)用到其他癌癥上,。研究人員稱下一步打算在較大的模式動物上測試這種優(yōu)化過的aptamer-siRNA化合物。（生物谷Bioon.com）
推薦相關(guān)閱讀：
全球RNAi藥物研發(fā)卡在藥物遞送
生物谷張發(fā)寶博士：Advance in RNAi delivery
生物谷專題匯總：RNAi
生物谷推薦原始出處：
Nature Biotechnology 27, 839 - 846 (2009) 23 August 2009 | doi:10.1038/nbt.1560
Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors
Justin P Dassie1,2,5, Xiu-ying Liu1,5, Gregory S Thomas1,2,5, Ryan M Whitaker1, Kristina W Thiel1, Katie R Stockdale1, David K Meyerholz3, Anton P McCaffrey1,2, James O McNamara II1 & Paloma H Giangrande1,2,4
Prostate cancer cells expressing prostate-specific membrane antigen (PSMA) have been targeted with RNA aptamer–small interfering (si)RNA chimeras, but therapeutic efficacy in vivo was demonstrated only with intratumoral injection. Clinical translation of this approach will require chimeras that are effective when administered systemically and are amenable to chemical synthesis. To these ends, we enhanced the silencing activity and specificity of aptamer-siRNA chimeras by incorporating modifications that enable more efficient processing of the siRNA by the cellular machinery. These included adding 2-nucleotide 3'-overhangs and optimizing the thermodynamic profile and structure of the duplex to favor processing of the siRNA guide strand. We also truncated the aptamer portion of the chimeras to facilitate large-scale chemical synthesis. The optimized chimeras resulted in pronounced regression of PSMA-expressing tumors in athymic mice after systemic administration. Anti-tumor activity was further enhanced by appending a polyethylene glycol moiety, which increased the chimeras' circulating half-life.
1.Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
2.Molecular and Cellular Biology Program, University of Iowa, Iowa City, Iowa, USA.
3.Department of Pathology, University of Iowa, Iowa City, Iowa, USA.
4.Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA.
5.These authors contributed equally to this work.
