Oligonucleotide-functionalized gold nanoparticles for synchronous telomerase inhibition, radiosensitization, and delivery of theranostic radionuclides

Bavelaar, B. M. et al. (2021) Oligonucleotide-functionalized gold nanoparticles for synchronous telomerase inhibition, radiosensitization, and delivery of theranostic radionuclides. Molecular Pharmaceutics, (doi: 10.1021/acs.molpharmaceut.1c00442) (Early Online Publication)

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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.

Item Type:Articles
Keywords:Drug discovery, pharmaceutical science, molecular medicine.
Status:Early Online Publication
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jackson, Dr Mark
Authors: Bavelaar, B. M., Song, L., Jackson, M. R., Able, S., Tietz, O., Skaripa-Koukelli, I., Waghorn, P. A., Gill, M. R., Carlisle, R. C., Tarsounas, M., and Vallis, K. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Pharmaceutics
Publisher:American Chemical Society (ACS)
ISSN:1543-8384
ISSN (Online):1543-8392
Published Online:27 August 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Molecular Pharmaceutics 2021
Publisher Policy:Reproduced under a Creative Commons licence

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