Open AccessOligonucleotide-Functionalized Gold Nanoparticles for Synchronous Telomerase Inhibition, Radiosensitization, and Delivery of Theranostic Radionuclides
Author(s) -
Bas M. Bavelaar,
Lei Song,
Mark R. Jackson,
Sarah Able,
Ole Tietz,
Irini Skaripa-Koukelli,
Philip A. Waghorn,
Martin R. Gill,
Robert Carlisle,
Madalena Tarsounas,
Katherine A. Vallis
Publication year - 2021
Publication title -
molecular pharmaceutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.13
H-Index - 127
eISSN - 1543-8392
pISSN - 1543-8384
DOI - 10.1021/acs.molpharmaceut.1c00442
Subject(s) - oligonucleotide , telomerase , chemistry , colloidal gold , cancer cell , cancer research , microbiology and biotechnology , biophysics , nanoparticle , cancer , dna , biochemistry , biology , nanotechnology , materials science , gene , genetics
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 111 In-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. 111 In-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 111 In-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.