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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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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa58013
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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) 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.
Keywords: telomerase, targeted radionuclide therapy, gold nanoparticles, Auger electrons, nanomedicine
College: Faculty of Science and Engineering
Funders: 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).
Issue: 10
Start Page: 3820
End Page: 3831