Systemic administration and targeted radiosensitization via chemically synthetic aptamer-siRNA chimeras in human tumor xenografts
Menée in vitro et à l'aide de xénogreffes de tumeur humaine, cette étude met en évidence l'intérêt d'un aptamère chimérique, constitué de petits ARNs interférents et administré par voie intraveineuse, pour sensibiliser aux rayonnements ionisants les cellules tumorales porteuses de l'antigène membranaire spécifique de la prostate
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.
http://mct.aacrjournals.org/content/early/2015/10/02/1535-7163.MCT-15-0291-T.abstract 2015