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Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors

chuanzhang116 添加于 2010-4-15 19:14 | 1810 次阅读 | 0 个评论

作者
Dassie JP, Liu X-ying, Thomas GS, Whitaker RM, Thiel KW, Stockdale KR, Meyerholz DK, McCaffrey AP, McNamara JO, Giangrande PH
摘要
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.
详细资料
- 文献种类:期刊
- 期刊名称: Nature Biotechnology
- 期刊缩写: Nat Biotechnol
- 期卷页: 2009年第27卷第9期 839-846页
- ISBN: 1087-0156
标签

siRNA
相关链接 DOI URL