Systemic administration and targeted radiosensitization via chemically synthetic aptamer-siRNA chimeras in human tumor xenografts

Xiaohua Ni, Yonggang Zhang, Kenji Zennami, Mark Castanares, Amarnath Mukherjee, Raju R. Raval, Haoming Zhou, Theodore L. Deweese, Shawn E. Lupold

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 prostatespecific 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 radiationmediated cell death. Following intravenous injection, the chimera effectively knocked down DNA-PK in established subcutaneous PSMA-positive tumors. Systemic treatment with these radiationsensitizing agents selectively enhanced the potency of external beam radiation therapy for established PSMA-positive tumors.

Original languageEnglish (US)
Pages (from-to)2797-2804
Number of pages8
JournalMolecular Cancer Therapeutics
Volume14
Issue number12
DOIs
StatePublished - Dec 1 2015
Externally publishedYes

Fingerprint

Heterografts
Small Interfering RNA
Membranes
Neoplasm Antigens
Neoplasms
Transfection
DNA
Prostatic Neoplasms
Radiotherapy
Nucleotide Aptamers
Radiation-Sensitizing Agents
Antigens
Palliative Care
Intravenous Injections
Nucleic Acids
Cell Death
Radiation
Neoplasm Metastasis
Bone and Bones
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Systemic administration and targeted radiosensitization via chemically synthetic aptamer-siRNA chimeras in human tumor xenografts. / Ni, Xiaohua; Zhang, Yonggang; Zennami, Kenji; Castanares, Mark; Mukherjee, Amarnath; Raval, Raju R.; Zhou, Haoming; Deweese, Theodore L.; Lupold, Shawn E.

In: Molecular Cancer Therapeutics, Vol. 14, No. 12, 01.12.2015, p. 2797-2804.

Research output: Contribution to journalArticle

Ni, Xiaohua ; Zhang, Yonggang ; Zennami, Kenji ; Castanares, Mark ; Mukherjee, Amarnath ; Raval, Raju R. ; Zhou, Haoming ; Deweese, Theodore L. ; Lupold, Shawn E. / Systemic administration and targeted radiosensitization via chemically synthetic aptamer-siRNA chimeras in human tumor xenografts. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 12. pp. 2797-2804.
@article{513d95df31b8466e8309abf6b9caff96,
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 prostatespecific 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 radiationmediated cell death. Following intravenous injection, the chimera effectively knocked down DNA-PK in established subcutaneous PSMA-positive tumors. Systemic treatment with these radiationsensitizing agents selectively enhanced the potency of external beam radiation therapy for established PSMA-positive tumors.",
author = "Xiaohua Ni and Yonggang Zhang and Kenji Zennami and Mark Castanares and Amarnath Mukherjee and Raval, {Raju R.} and Haoming Zhou and Deweese, {Theodore L.} and Lupold, {Shawn E.}",
year = "2015",
month = "12",
day = "1",
doi = "10.1158/1535-7163.MCT-15-0291-T",
language = "English (US)",
volume = "14",
pages = "2797--2804",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Systemic administration and targeted radiosensitization via chemically synthetic aptamer-siRNA chimeras in human tumor xenografts

AU - Ni, Xiaohua

AU - Zhang, Yonggang

AU - Zennami, Kenji

AU - Castanares, Mark

AU - Mukherjee, Amarnath

AU - Raval, Raju R.

AU - Zhou, Haoming

AU - Deweese, Theodore L.

AU - Lupold, Shawn E.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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 prostatespecific 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 radiationmediated cell death. Following intravenous injection, the chimera effectively knocked down DNA-PK in established subcutaneous PSMA-positive tumors. Systemic treatment with these radiationsensitizing agents selectively enhanced the potency of external beam radiation therapy for established PSMA-positive tumors.

AB - 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 prostatespecific 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 radiationmediated cell death. Following intravenous injection, the chimera effectively knocked down DNA-PK in established subcutaneous PSMA-positive tumors. Systemic treatment with these radiationsensitizing agents selectively enhanced the potency of external beam radiation therapy for established PSMA-positive tumors.

UR - http://www.scopus.com/inward/record.url?scp=84958073864&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958073864&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-15-0291-T

DO - 10.1158/1535-7163.MCT-15-0291-T

M3 - Article

C2 - 26438155

AN - SCOPUS:84958073864

VL - 14

SP - 2797

EP - 2804

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 12

ER -