Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts
Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts
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DOI：
10.1172/jci45109
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发表时间：
2011-06-01
影响因子：
15.9
通讯作者：
Lupold, Shawn E.
中科院分区：
文献类型：
--
作者：
Ni, Xiaohua;Zhang, Yonggang;Lupold, Shawn E.
局部前列腺癌（PCa）的剂量递增放射治疗具有明显的治疗益处;然而，剂量递增也可能增加对非癌组织的损伤。放射增敏剂可以提高电离辐射（IR）效力，但如果没有靶向递送，这些试剂也会使周围正常组织敏化。在这里，我们描述了前列腺靶向RNAi剂的发展，选择性致敏前列腺特异性膜抗原阳性（PSMA阳性）细胞的IR。siRNA文库筛选确定DNA活化蛋白激酶，催化多肽（DNAPK）作为一个理想的放射增敏目标。通过PSMA靶向RNA适体递送的DNAPK shRNA选择性地减少PCa细胞、异种移植物和人前列腺组织中的DNAPK。适体靶向DNAPK的shRNA，结合IR，显着和特异性增强PSMA阳性肿瘤对IR的反应。这些研究结果支持适体-shRNA嵌合体作为选择性增敏剂，用于改善治疗高危局部PCa。
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.