Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors.
Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors.
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DOI：
10.1038/nbt.1560
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发表时间：
2009-09
影响因子：
46.9
通讯作者：
Giangrande, Paloma H.
中科院分区：
文献类型：
--
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.
表达前列腺特异性膜抗原（PSMA）的前列腺癌细胞已经被RNA适体-小干扰（si）RNA嵌合体靶向，但体内治疗功效仅通过瘤内注射来证明。这种方法的临床转化将需要嵌合体，这些嵌合体在全身给药时有效并且易于化学合成。为了这些目的，我们通过掺入能够使siRNA被细胞机器更有效加工的修饰来增强适体-siRNA嵌合体的沉默活性和特异性。这些包括添加2个核苷酸的3 ′-突出端和优化双链体的热力学特征和结构，以有利于siRNA引导链的加工。我们还截短了嵌合体的适体部分，以促进大规模的化学合成。优化的嵌合体在全身给药后导致无胸腺小鼠中PSMA表达肿瘤的显著消退。抗肿瘤活性通过附加聚乙二醇部分进一步增强，这增加了嵌合体的循环半衰期。
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.
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