Ni Xiaohua, Zhang Yonggang, Zennami Kenji, Castanares Mark, Mukherjee Amarnath, Raval Raju R, Zhou Haoming, DeWeese Theodore L, Lupold Shawn E
The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland. Shanghai Institute of Planned Parenthood Research, National Population and Family Planning Key Laboratory of Contraceptive Drugs and Devices, Shanghai, China.
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.
Mol Cancer Ther. 2015 Dec;14(12):2797-804. doi: 10.1158/1535-7163.MCT-15-0291-T. Epub 2015 Oct 5.
Radiation therapy is a highly effective tool for treating all stages of prostate cancer, 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 that 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.
放射治疗是治疗前列腺癌各个阶段的一种高效工具，从针对局限性疾病的根治性方法到姑息治疗以及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得到提高。适体是用于短发夹RNA（shRNA）和小干扰RNA（siRNA）的有前景的核酸递送剂。我们之前开发了一种放射增敏性RNA适体-shRNA嵌合体，在无转染试剂的情况下，它能将靶向DNA-PK的shRNAs选择性递送至前列腺特异性膜抗原（PSMA）阳性细胞。尽管这些嵌合体有效，但其合成需要体外转录，且其评估仅限于瘤内给药。在此，我们开发了第二代适体-siRNA嵌合体，它可通过三个单独化学合成组分的退火进行组装。所得嵌合体在PSMA阳性前列腺癌细胞中敲低DNA-PK，无需额外的转染试剂，并增强了放射介导的细胞死亡的效力。静脉注射后，该嵌合体有效敲低已建立的皮下PSMA阳性肿瘤中的DNA-PK。用这些放射增敏剂进行全身治疗可选择性增强针对已建立的PSMA阳性肿瘤的外照射放疗的效力。
