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

Publication ,  Journal Article
Dassie, JP; Liu, X-Y; Thomas, GS; Whitaker, RM; Thiel, KW; Stockdale, KR; Meyerholz, DK; McCaffrey, AP; McNamara, JO; Giangrande, PH
Published in: Nat Biotechnol
September 2009

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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Published In

Nat Biotechnol

DOI

EISSN

1546-1696

Publication Date

September 2009

Volume

27

Issue

9

Start / End Page

839 / 849

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • RNA, Small Interfering
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Polo-Like Kinase 1
  • Nucleic Acid Conformation
  • Mice, Nude
  • Mice
  • Male
 

Citation

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Dassie, J. P., Liu, X.-Y., Thomas, G. S., Whitaker, R. M., Thiel, K. W., Stockdale, K. R., … Giangrande, P. H. (2009). Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol, 27(9), 839–849. https://doi.org/10.1038/nbt.1560
Dassie, Justin P., 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. “Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors.Nat Biotechnol 27, no. 9 (September 2009): 839–49. https://doi.org/10.1038/nbt.1560.
Dassie JP, Liu X-Y, Thomas GS, Whitaker RM, Thiel KW, Stockdale KR, et al. Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol. 2009 Sep;27(9):839–49.
Dassie, Justin P., et al. “Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors.Nat Biotechnol, vol. 27, no. 9, Sept. 2009, pp. 839–49. Pubmed, doi:10.1038/nbt.1560.
Dassie JP, Liu X-Y, Thomas GS, Whitaker RM, Thiel KW, Stockdale KR, Meyerholz DK, McCaffrey AP, McNamara JO, Giangrande PH. Systemic administration of optimized aptamer-siRNA chimeras promotes regression of PSMA-expressing tumors. Nat Biotechnol. 2009 Sep;27(9):839–849.

Published In

Nat Biotechnol

DOI

EISSN

1546-1696

Publication Date

September 2009

Volume

27

Issue

9

Start / End Page

839 / 849

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • RNA, Small Interfering
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Prostatic Neoplasms
  • Polo-Like Kinase 1
  • Nucleic Acid Conformation
  • Mice, Nude
  • Mice
  • Male