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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2383-2390
Number of pages8
JournalJournal of Clinical Investigation
Volume121
Issue number6
DOIs
StatePublished - Jun 1 2011

ASJC Scopus subject areas

  • Medicine(all)

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