Evaluation of gold nanoparticles as radiosensitizing agents for high dose rate brachytherapy
| dc.contributor.author | Cecchi, Daniel | |
| dc.contributor.supervisor | Chithrani, Devika | |
| dc.date.accessioned | 2026-05-21T20:55:55Z | |
| dc.date.available | 2026-05-21T20:55:55Z | |
| dc.date.issued | 2026 | |
| dc.degree.department | Department of Physics and Astronomy | |
| dc.degree.level | Doctor of Philosophy PhD | |
| dc.description.abstract | Radiation therapy (RT) is a pivotal part of more than half of all cancer patients’ treatment plan. Despite its clinical effectiveness, normal tissue toxicity remains a fundamental limitation, restricting dose escalation to the tumour and constraining tumour control. Radiosensitizers like gold nanoparticles (GNPs) offer a potential strategy to locally enhance dose deposition in tumour tissue. Due to their high atomic number, GNP-mediated radiosensitization is pronounced at lower photon energies, where increased photoelectric interactions lead to a greater generation of secondary, cell-damaging species. Compared to high-energy external beam radiotherapy (EBRT) (≈1-10 MeV), high dose rate brachytherapy (HDR-BT), which employs radioactive sources emitting low to intermediate-energy photons (≈ 0.1-0.5 MeV), may be an ideal candidate for the introduction of GNPs as radiosensitizing agents. However, preclinical investigations of GNP-induced radiosensitization in HDR-BT remains scarce, largely due to technical challenges of dose delivery in vitro and in vivo due to steep dose gradients and complex treatment delivery. This dissertation addresses these limitations by developing novel irradiation platforms to facilitate robust pre-clinical investigations of GNP-mediated radiosensitization in HDR-BT. We first developed a novel Solid Water plastic phantom to enable uniform HDR-BT irradiation to the base of a petri dish containing cell cultures. Dosimetric verification demonstrated accurate dose delivery and acceptable uniformity across the petri dish within ±5%. Using this platform, GNP-mediated radiosensitization was evaluated during irradiations from both HDR-BT and EBRT to assess energy dependent differences in radiosensitizing efficacy. We found that under HDR-BT, GNPs elicit effective radiosensitization, evidenced by an increase in 53BP1-related DNA damage foci between 30-100% and a marked reduction in clonogenic survival between 2-5%. When the delivered dose rate was matched between HDR-BT and EBRT irradiations, comparable levels of GNP-induced radiosensitization were observed, indicating a dose-rate-dependent component independent of beam energy. In addition, radioactive decay during the clinical lifetime of HDR-BT sources was found to significantly reduce GNP radiosensitization, with the clonogenic survival decrease diminishing from ≈15% with a high-strength source to no measurable enhancement during low source-strength radiations. Next, we optimized the route of administration and functionalization strategy to maximize tumour accumulation and retention in vivo. Intratumoural (i.t.) uptake iv of PEGylated and RGD-functionalized GNPs were investigated following intravenous (i.v.) and i.t. delivery. Both PEGylation alone and RGD functionalization resulted in poor tumour accumulation after i.v. injection but high tumour accumulation and retention following i.t. administration, indicating the viability of either functionalization strategy to be retained within the tumour tissue post-i.t. injections. This work supports the feasibility of i.t. GNP delivery in future HDR-BT workflows. Finally, in vivo irradiations were accomplished using a novel 3-D printed, non invasive irradiation jig designed to encompass the lateral side of tumour-bearing mice. Dosimetric verification revealed accurate tumour dose delivery with minimal toxicity concerns to tumour-bearing mice. PEGylated and RGD functionalized GNPs were subsequently investigated following i.t. administration and compared to in vitro radiosensitization outcomes. Consistent across both in vitro and in vivo experiments, PEGylated GNPs did not produce measurable radiosensitization. In contrast, RGD functionalized GNPs, which promotes intracellular uptake with active receptor targeting, resulted in a significant 20% increase in DNA damage, 20% reduction in clonogenic survival, 57% stunted growth in tumour spheroids, and a pronounced 50% tumour growth delay following HDR-BT relative to control. These findings demonstrate the efficacy of targeted GNP radiosensitization in HDR-BT and demands further investigation into their translational safety and toxicity profiles. | |
| dc.description.scholarlevel | Graduate | |
| dc.identifier.uri | https://hdl.handle.net/1828/23926 | |
| dc.language | English | eng |
| dc.language.iso | en | |
| dc.rights | Attribution-NonCommercial 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | |
| dc.title | Evaluation of gold nanoparticles as radiosensitizing agents for high dose rate brachytherapy | |
| dc.type | Thesis |