title: Systemic Administration and Targeted Radiosensitization via Chemically Synthetic Aptamer-siRNA Chimeras in Human Tumor Xenografts.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Ni
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Kenji
authors.initials: K
authors.lastname: Zennami
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Castanares
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Amarnath
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Raju R
authors.initials: RR
authors.lastname: Raval
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Haoming
authors.initials: H
authors.lastname: Zhou
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Theodore L
authors.initials: TL
authors.lastname: DeWeese
authors.affiliation: The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland. Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. slupold@jhmi.edu.
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Lupold
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics*; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000138:chemical synthesis / Q000235:genetics; D045744:Cell Line, Tumor; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000138:chemical synthesis / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000138:chemical synthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D052157:Aptamers, Nucleotide; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II