Oligonucleotide-functionalized gold nanoparticles for synchronous telomerase inhibition, radiosensitization, and delivery of theranostic radionuclides
| Autor: | Ole Tietz, Philip A. Waghorn, Robert Carlisle, Mark R. Jackson, Lei Song, Martin R. Gill, Irini Skaripa-Koukelli, Madalena Tarsounas, Bas M. Bavelaar, Sarah Able, Katherine A. Vallis |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Telomerase
Protein subunit Oligonucleotides Metal Nanoparticles Pharmaceutical Science Peptide telomerase Article chemistry.chemical_compound Microscopy Electron Transmission Cell Line Tumor Drug Discovery Humans chemistry.chemical_classification Microscopy Confocal Oligonucleotide targeted radionuclide therapy nanomedicine chemistry Colloidal gold gold nanoparticles Cancer cell Biophysics Molecular Medicine Nanomedicine Gold Auger electrons Nanoparticle Drug Delivery System DNA |
| Zdroj: | Molecular Pharmaceutics |
| ISSN: | 1543-8384 |
| Popis: | 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) for111In-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, and111In–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. |
| Databáze: | OpenAIRE |
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