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.