Systemic Administration and Targeted Radiosensitization via Chemically Synthetic Aptamer-siRNA Chimeras in Human Tumor Xenografts.
Systemic Administration and Targeted Radiosensitization via Chemically Synthetic Aptamer-siRNA Chimeras in Human Tumor Xenografts.
复制标题
通过化学合成适体-siRNA 嵌合体在人类肿瘤异种移植物中进行全身给药和靶向放射增敏。
DOI：
10.1158/1535-7163.mct-15-0291-t
复制
发表时间：
2015-12
影响因子：
5.7
通讯作者：
Lupold SE
中科院分区：
文献类型：
--
作者：
Ni X;Zhang Y;Zennami K;Castanares M;Mukherjee A;Raval RR;Zhou H;DeWeese TL;Lupold SE
放射治疗是治疗前列腺癌（PCa）所有阶段的高效工具，从局部疾病的治愈方法到姑息治疗和提高远处骨转移患者的生存率。这些方法的治疗指数可以通过靶向放射增敏剂来增强。核酸适体是一种很有前途的短干扰RNA（siRNA）和短发夹RNA（shRNA）的核酸载体。我们先前已经开发了一种辐射增敏RNA适体-shRNA嵌合体，其在不存在转染试剂的情况下选择性地将DNA-PK靶向shRNA递送至前列腺特异性膜抗原（PSMA）阳性细胞。虽然这些嵌合体是有效的，但它们的合成需要体外转录，并且它们的评价仅限于瘤内给药。在这里，我们开发了第二代适体-siRNA嵌合体，其可以通过三个单独的化学合成组分的退火来组装。所得到的嵌合体在PSMA阳性前列腺癌细胞中敲低DNA-PK，而不需要额外的转染试剂，并增强了辐射介导的细胞死亡的功效。静脉注射后，嵌合体有效地敲低了已建立的皮下PSMA阳性肿瘤中的DNA-PK。这些放射增敏剂的全身治疗选择性地增强了外照射放射治疗对已建立的PSMA阳性肿瘤的效力。
Radiation therapy is a highly effective tool for treating all stages of prostate cancer (PCa), from curative approaches in localized disease to palliative care and enhanced survival for patients with distant bone metastases. The therapeutic index of these approaches may be enhanced with targeted radiation-sensitizing agents. Aptamers are promising nucleic-acid delivery agents for short interfering RNAs (siRNA) and short hairpin RNAs (shRNA). We have previously developed a radiation-sensitizing RNA aptamer-shRNA chimera which selectively delivers DNA-PK targeting shRNAs to Prostate Specific Membrane Antigen (PSMA) positive cells in the absence of transfection reagents. Although these chimera are effective, their synthesis requires in vitro transcription and their evaluation was limited to intratumoral administration. Here we have developed a second generation aptamer-siRNA chimera that can be assembled through the annealing of three separate chemically synthesized components. The resulting chimera knocked-down DNA-PK in PSMA-positive prostate cancer cells, without the need of additional transfection reagents, and enhanced the efficacy of radiation mediated cell death. Following intravenous injection, the chimera effectively knocked down DNA-PK in established subcutaneous PSMA-positive tumors. Systemic treatment with these radiation-sensitizing agents selectively enhanced the potency of external beam radiation therapy for established PSMA-positive tumors.