Evaluation of gold nanoparticles and docetaxel as radiosensitizing agents to improve current radiotherapy treatments
Date
2026
Authors
Jackson, Nolan
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Abstract
Radiotherapy (RT) remains an important form of cancer treatment in the regimens for many cancer patients. Despite substantial technological advancements in external beam radiotherapy (EBRT), tumor control and long-term survival outcomes can remain sub-optimal. A primary limitation arises from normal tissue toxicities, which constrain the maximum radiation dose that can be safely delivered. As a result, strategies that can enhance tumor response without increasing the administered dose are highly desirable. Radiosensitizers represent one such approach, offering the potential to improve the therapeutic ratio by increasing tumor sensitivity to radiation. In this context, gold nanoparticles (GNPs) and docetaxel (DTX) present a promising combination, leveraging complementary physical and biological mechanisms to enhance the effects of RT.
The initial evaluation of this strategy was conducted using monolayer cell culture models to assess mechanistic insight. DTX treatment was shown to induce cell cycle synchronization in the G2/M phase, a stage known to exhibit increased radiosensitivity. In addition to these effects, DTX significantly enhanced the intracellular accumulation of GNPs, with PC-3 and MIA PaCa-2 cells demonstrating 34% and 49% increases in GNP concentration, respectively, compared to untreated controls 24 h after exposure to both agents. When combined with RT delivered using a clinically relevant 6 MV linear accelerator, this resulted in an enhanced radiation response, with the combined treatment increasing DNA damage foci by approximately 80% and 130% in PC-3 and MIA PaCa-2 cells, respectively. This was further associated with reduced cellular proliferation, where the addition of GNPs to DTX-treated cells combined with RT reduced cell growth by 15% and 10% three days after irradiation. These findings demonstrated that the combination of GNPs and DTX can effectively enhance radiosensitivity under controlled in vitro conditions.
To further evaluate the translational potential of this approach, studies were extended to more physiologically relevant models, including 3D spheroids and in vivo xenograft tumors. Spheroid models incorporate key features of the tumor microenvironment (TME), such as extracellular matrix deposition, cell–cell interactions, and concentration gradients, which introduce barriers to nanoparticle
(NP) penetration and influence treatment response. Despite these additional barriers, DTX retained its ability to induce cell cycle arrest and continued to enhance GNP accumulation. Importantly, the combined GNP/DTX strategy improved response to RT in spheroid models, where the addition of GNPs to DTX/RT resulted in a 20% reduction in spheroid size in both MIA PaCa-2 and PC-3 models compared to DTX/RT alone. These findings were further supported in xenograft tumors, where DTX increased tumor GNP accumulation by greater than 100% at 24 h post-injection. This translated
into improved tumor response to RT, with the triple combination reducing tumor growth by 34% in MIA PaCa-2 tumors and 54% in PC-3 tumors compared to RT alone, reinforcing the potential applicability of this strategy in more complex biological systems.
Recognizing the limitations of immunocompromised models, the final component of this work investigated GNP biodistribution in immunocompetent, syngeneic tumor models. The presence of an intact immune system was found to significantly alter GNP distribution, resulting in reduced tumor accumulation and increased sequestration in organs such as the liver and spleen. Specifically, less than 1% of the injected dose remained in the plasma 8 h post-injection, and GNP accumulation in KPCY tumors was reduced by 57% compared to MIA PaCa-2 tumors grown in NRG mice. However, DTX was still able to partially improve delivery in this setting, increasing GNP concentration in KPCY tumors by 67% and 75% at 24 h and 48 h post-injection, respectively. Additionally, surface functionalization strategies, including RGD targeting, were shown to influence immune recognition and GNP localization, where RGD-functionalized GNPs demonstrated a greater than 10-fold decrease in tumor accumulation and a 99% reduction in plasma concentration compared to GNP-PEG complexes. These findings highlight the critical role of immune-mediated processes in governing GNP delivery and underscore the importance of evaluating such strategies in immunocompetent models. Collectively, this work demonstrates the potential of combining GNPs and DTX as radiosensitizers while emphasizing the need to consider
biological context to optimize their translational success.