Research abstract
Article abstract
Nature Biotechnology 27, 839 - 846 (2009)
Published online: 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
Abstract
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.
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
- Molecular and Cellular Biology Program, University of Iowa, Iowa City, Iowa, USA.
- Department of Pathology, University of Iowa, Iowa City, Iowa, USA.
- Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, USA.
- These authors contributed equally to this work.
Correspondence to: Paloma H Giangrande1,2,4 e-mail: paloma-giangrande@uiowa.edu
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