@article{bd47481303954300806bef5159dd369f,
title = "Tunable cytotoxic aptamer–drug conjugates for the treatment of prostate cancer",
abstract = "Therapies that can eliminate both local and metastatic prostate tumor lesions while sparing normal organ tissue are desperately needed. With the goal of developing an improved drug-targeting strategy, we turned to a new class of targeted anticancer therapeutics: aptamers conjugated to highly toxic chemotherapeutics. Cell selection for aptamers with prostate cancer specificity yielded the E3 aptamer, which internalizes into prostate cancer cells without targeting normal prostate cells. Chemical conjugation of E3 to the drugs monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) yields a potent cytotoxic agent that efficiently kills prostate cancer cells in vitro but does not affect normal prostate epithelial cells. Importantly, the E3 aptamer targets tumors in vivo and treatment with the MMAF-E3 conjugate significantly inhibits prostate cancer growth in mice, demonstrating the in vivo utility of aptamer–drug conjugates. Additionally, we report the use of antidotes to block E3 aptamer–drug conjugate cytotoxicity, providing a safety switch in the unexpected event of normal cell killing in vivo.",
keywords = "Antidote control, Aptamer, Aptamer–drug conjugate, Drug targeting, Prostate cancer",
author = "Gray, {Bethany Powell} and Linsley Kelly and Ahrens, {Douglas P.} and Barry, {Ashley P.} and Christina Kratschmer and Matthew Levy and Sullenger, {Bruce A.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Keith E. Maier for his assistance with oligonucleotide synthesis. This work was supported by Department of Defense (DoD) Prostate Cancer Research Program (PCRP) Postdoctoral Training Award PC131874 (to B.P.G.) and Synergistic Idea Award PC111812P2/ W81XWH-12-1-0262 (to B.A.S.); Stand Up to Cancer Innovative Research Grant SU2C-AACR-IRG-0809 (to M.L.); and National Cancer Institute (NCI) Grants R21CA182330 (to M.L.) and R21CA157366-03 (to M.L.). Additionally, this work was supported by Duke Cancer Institute (DCI) NCI Grant P30-CA014236 funding for the Duke Optical Molecular Imaging and Analysis Facility (in vivo imaging), DCI Flow Cytometry Shared Resource (flow cytometry), and Duke Light Microscopy Core Facility (confocal microscopy). Funding Information: We thank Keith E. Maier for his assistance with oligonucleotide synthesis. This work was supported by Department of Defense (DoD) Prostate Cancer Research Program (PCRP) Postdoctoral Training Award PC131874 (to B.P.G.) and Synergistic Idea Award PC111812P2/ W81XWH-12-1-0262 (to B.A.S.); Stand Up to Cancer Innovative Research Grant SU2C-AACR-IRG-0809 (to M.L.); and National Cancer Institute (NCI) Grants R21CA182330 (to M.L.) and R21CA157366-03 (to M.L.). Additionally, this work was supported by Duke Cancer Institute (DCI) NCI Grant P30-CA014236 funding for the Duke Optical Molecular Imaging and Analysis Facility (in vivo imaging), DCI Flow Cytometry Shared Resource (flow cytometry), and Duke Light Microscopy Core Facility (confocal microscopy). Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All rights reserved.",
year = "2018",
month = may,
day = "1",
doi = "10.1073/pnas.1717705115",
language = "English (US)",
volume = "115",
pages = "4761--4766",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "18",
}