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Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides

Bas M. Bavelaar, Lei Song, Mark R. Jackson, Sarah Able, Ole Tietz, Irini Skaripa-Koukelli, Philip A. Waghorn, Martin Gill Orcid Logo, Robert C. Carlisle, Madalena Tarsounas, Katherine A. Vallis

Molecular Pharmaceutics, Volume: 18, Issue: 10, Pages: 3820 - 3831

Swansea University Author: Martin Gill Orcid Logo

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DOI (Published version): 10.1021/acs.molpharmaceut.1c00442

Abstract

Telomerase represents an attractive target in oncology as it is expressed in cancer but not in normal tissues. The oligonucleotide inhibitors of telomerase represent a promising anticancer strategy, although poor cellular uptake can restrict their efficacy. In this study, gold nanoparticles (AuNPs)...

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Published in: Molecular Pharmaceutics
ISSN: 1543-8384 1543-8392
Published: American Chemical Society (ACS) 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa58013
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spelling 2022-10-28T15:17:03.1421880 v2 58013 2021-09-22 Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides 485d85b532851e8863cd19c6af7e00f7 0000-0002-1371-5676 Martin Gill Martin Gill true false 2021-09-22 CHEM Telomerase represents an attractive target in oncology as it is expressed in cancer but not in normal tissues. The oligonucleotide inhibitors of telomerase represent a promising anticancer strategy, although poor cellular uptake can restrict their efficacy. In this study, gold nanoparticles (AuNPs) were used to enhance oligonucleotide uptake. “match” oligonucleotides complementary to the telomerase RNA template subunit (hTR) and “scramble” (control) oligonucleotides were conjugated to diethylenetriamine pentaacetate (DTPA) for 111In-labeling. AuNPs (15.5 nm) were decorated with a monofunctional layer of oligonucleotides (ON–AuNP) or a multifunctional layer of oligonucleotides, PEG(polethylene glycol)800-SH (to reduce AuNP aggregation) and the cell-penetrating peptide Tat (ON–AuNP–Tat). Match–AuNP enhanced the cellular uptake of radiolabeled oligonucleotides while retaining the ability to inhibit telomerase activity. The addition of Tat to AuNPs increased nuclear localization. 111In–Match–AuNP–Tat induced DNA double-strand breaks and caused a dose-dependent reduction in clonogenic survival of telomerase-positive cells but not telomerase-negative cells. hTR inhibition has been reported to sensitize cancer cells to ionizing radiation, and 111In–Match–AuNP–Tat therefore holds promise as a vector for delivery of radionuclides into cancer cells while simultaneously sensitizing them to the effects of the emitted radiation. Journal Article Molecular Pharmaceutics 18 10 3820 3831 American Chemical Society (ACS) 1543-8384 1543-8392 telomerase, targeted radionuclide therapy, gold nanoparticles, Auger electrons, nanomedicine 4 10 2021 2021-10-04 10.1021/acs.molpharmaceut.1c00442 COLLEGE NANME Chemistry COLLEGE CODE CHEM Swansea University Another institution paid the OA fee The authors gratefully acknowledge funding support from Cancer Research-UK (C5255/A15935), the Engineering and Physical Sciences Research Council (EPSRC) Oxford Centre for Drug Delivery Devices (EP/L024012/1), and the CRUK/EPSRC Cancer Imaging Centre Oxford (C5255/A16466). 2022-10-28T15:17:03.1421880 2021-09-22T17:37:14.0848870 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Bas M. Bavelaar 1 Lei Song 2 Mark R. Jackson 3 Sarah Able 4 Ole Tietz 5 Irini Skaripa-Koukelli 6 Philip A. Waghorn 7 Martin Gill 0000-0002-1371-5676 8 Robert C. Carlisle 9 Madalena Tarsounas 10 Katherine A. Vallis 11 58013__21262__5785ee523db444b0a510de8ee44f6db8.pdf 58013.pdf 2021-10-21T14:12:22.0189724 Output 3446635 application/pdf Version of Record true © 2021 The Authors. Released under the terms of a Creative Commons Attribution 4.0 International (CC BY 4.0) License true eng https://creativecommons.org/licenses/by/4.0/
title Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides
spellingShingle Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides
Martin Gill
title_short Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides
title_full Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides
title_fullStr Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides
title_full_unstemmed Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides
title_sort Oligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides
author_id_str_mv 485d85b532851e8863cd19c6af7e00f7
author_id_fullname_str_mv 485d85b532851e8863cd19c6af7e00f7_***_Martin Gill
author Martin Gill
author2 Bas M. Bavelaar
Lei Song
Mark R. Jackson
Sarah Able
Ole Tietz
Irini Skaripa-Koukelli
Philip A. Waghorn
Martin Gill
Robert C. Carlisle
Madalena Tarsounas
Katherine A. Vallis
format Journal article
container_title Molecular Pharmaceutics
container_volume 18
container_issue 10
container_start_page 3820
publishDate 2021
institution Swansea University
issn 1543-8384
1543-8392
doi_str_mv 10.1021/acs.molpharmaceut.1c00442
publisher American Chemical Society (ACS)
college_str Faculty of Science and Engineering
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hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 1
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description Telomerase represents an attractive target in oncology as it is expressed in cancer but not in normal tissues. The oligonucleotide inhibitors of telomerase represent a promising anticancer strategy, although poor cellular uptake can restrict their efficacy. In this study, gold nanoparticles (AuNPs) were used to enhance oligonucleotide uptake. “match” oligonucleotides complementary to the telomerase RNA template subunit (hTR) and “scramble” (control) oligonucleotides were conjugated to diethylenetriamine pentaacetate (DTPA) for 111In-labeling. AuNPs (15.5 nm) were decorated with a monofunctional layer of oligonucleotides (ON–AuNP) or a multifunctional layer of oligonucleotides, PEG(polethylene glycol)800-SH (to reduce AuNP aggregation) and the cell-penetrating peptide Tat (ON–AuNP–Tat). Match–AuNP enhanced the cellular uptake of radiolabeled oligonucleotides while retaining the ability to inhibit telomerase activity. The addition of Tat to AuNPs increased nuclear localization. 111In–Match–AuNP–Tat induced DNA double-strand breaks and caused a dose-dependent reduction in clonogenic survival of telomerase-positive cells but not telomerase-negative cells. hTR inhibition has been reported to sensitize cancer cells to ionizing radiation, and 111In–Match–AuNP–Tat therefore holds promise as a vector for delivery of radionuclides into cancer cells while simultaneously sensitizing them to the effects of the emitted radiation.
published_date 2021-10-04T04:14:11Z
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