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

Justin P Dassie; Xiu-ying Liu; Gregory S Thomas; Ryan M Whitaker; Kristina W Thiel; Katie R Stockdale; David K Meyerholz; Anton P McCaffrey; James O McNamara; Paloma H Giangrande

doi:10.1038/nbt.1560

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

Journal article

Peer reviewed

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

Justin P Dassie, Xiu-ying Liu, Gregory S Thomas, Ryan M Whitaker, Kristina W Thiel, Katie R Stockdale, David K Meyerholz, Anton P McCaffrey, James O McNamara and Paloma H Giangrande

Nature biotechnology, Vol.27(9), pp.839-849

09/2009

DOI: 10.1038/nbt.1560

PMCID: PMC2791695

PMID: 19701187

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https://www.ncbi.nlm.nih.gov/pmc/articles/2791695View

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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.

Details

Title: Subtitle: Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors
Creators: Justin P Dassie - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Xiu-ying Liu - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Gregory S Thomas - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Ryan M Whitaker - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Kristina W Thiel - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Katie R Stockdale - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
David K Meyerholz - Department of Pathology, University of Iowa, Iowa City, Iowa, USA
Anton P McCaffrey - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
James O McNamara - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Paloma H Giangrande - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
Resource Type: Journal article
Publication Details: Nature biotechnology, Vol.27(9), pp.839-849
DOI: 10.1038/nbt.1560
PMID: 19701187
PMCID: PMC2791695
NLM abbreviation: Nat Biotechnol
ISSN: 1087-0156
eISSN: 1546-1696
Language: English
Date published: 09/2009
Academic Unit: Pathology; Radiation Oncology; Obstetrics and Gynecology; Medicine Administration; Internal Medicine
Record Identifier: 9984083234902771

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