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

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 In-111-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. In-111-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 In-111-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.

Automated summary

In this study, gold nanoparticles (AuNPs) were used to enhance cellular uptake of oligonucleotides targeting telomerase. The addition of Tat to AuNPs increased nuclear localization and induced DNA double-strand breaks in telomerase-positive cells. In-111-Match-AuNP-Tat shows promise as a vector for delivering radionuclides to cancer cells while sensitizing them to the effects of emitted radiation.