siRNA能够阻断细胞内可能发生的有害活动，如肿瘤细胞的生长。但是要成功地将siRNA传送到特异性的细胞中而不对其它细胞产生不利影响还一直是个难题。
美国爱荷华大学的研究人员通过修饰siRNA，使得将这种siRNA注射到血液后，能够特异性地影响靶细胞，并且降低对其他细胞的副作用。这项研究是在患前列腺癌的模式生物上完成的，或许有助于开发大量的针对癌症或其他疾病的治疗性的siRNA。这篇研究报告发表在8月23日的Nature Biotechnology杂志上。
之前，杜克大学Giangrande课题组的研究表明，一种名为aptamer的化合物可与siRNA结合使用靶向某些基因。当将这种结合使用的分子直接注射到动物模型的肿瘤中，发现它能够终止肿瘤的生长过程。但是，将其直接注射到人体肿瘤细胞中还存在一些问题。
在最近的这项研究中，研究人员将这种前列腺癌特异性的aptamer的大小进行削减，然后通过修饰siRNA以增强其活性。然后将二者结合注射到血液中，发现可以抑制肿瘤的生长并且对正常组织没有影响。
课题组还表示，因为多数siRNA在发挥功能之前可通过肾脏排出体外，因此siRNA的需要量非常大。为了保持siRNA在机体内存留时间更长，课题组利用一种称为“PEGlyation”的过程对siRNA进行修饰。
虽然目前的这项研究集中在对前列腺癌的研究，但这项发现或许还能应用到其他癌症上。研究人员称下一步打算在较大的模式动物上测试这种优化过的aptamer-siRNA化合物。（生物谷Bioon.com）
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全球RNAi药物研发卡在药物递送
生物谷张发宝博士：Advance in RNAi delivery
生物谷专题汇总：RNAi
生物谷推荐原始出处：
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.
