Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts

Ni, Xiaohua; Zhang, Yonggang; Ribas i Fortuny, Judit; Chowdhury, Wasim H.; Castanares, Mark; Zhang, Zhewei; Laiho, Marikki; DeWeese, Theodore L.; Lupold, Shawn E.

doi:https://doi.org/10.1172/JCI45109

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Fecha de publicación

2011

Autor/a

Ni, Xiaohua

Zhang, Yonggang

Ribas i Fortuny, Judit

Chowdhury, Wasim H.

Castanares, Mark

Zhang, Zhewei

Laiho, Marikki

DeWeese, Theodore L.

Lupold, Shawn E.

Cita recomendada

Ni, Xiaohua; Zhang, Yonggang; Ribas i Fortuny, Judit; Chowdhury, Wasim H.; Castanares, Mark; Zhang, Zhewei; ... Lupold, Shawn E.. (2011) . Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts. Journal of Clinical Investigation, 2011, vol. 121, núm. 6, p. 2383-2390. https://doi.org/10.1172/JCI45109.

Resumen

Dose-escalated radiation therapy for localized prostate cancer (PCa) has a clear therapeutic benefit; however, escalated doses may also increase injury to noncancerous tissues. Radiosensitizing agents can improve ionizing radiation (IR) potency, but without targeted delivery, these agents will also sensitize surrounding normal tissues. Here we describe the development of prostate-targeted RNAi agents that selectively sensitized prostate-specific membrane antigen–positive (PSMA-positive) cells to IR. siRNA library screens identified DNA-activated protein kinase, catalytic polypeptide (DNAPK) as an ideal radiosensitization target. DNAPK shRNAs, delivered by PSMA-targeting RNA aptamers, selectively reduced DNAPK in PCa cells, xenografts, and human prostate tissues. Aptamer-targeted DNAPK shRNAs, combined with IR, dramatically and specifically enhanced PSMA-positive tumor response to IR. These findings support aptamer-shRNA chimeras as selective sensitizing agents for the improved treatment of high-risk localized PCa.

URI

http://hdl.handle.net/10459.1/47333

DOI

https://doi.org/10.1172/JCI45109

Es parte de

Journal of Clinical Investigation, 2011, vol. 121, núm. 6, p. 2383-2390