Purpose: Gold nanoparticles (GNPs) are promising radiosensitizing agents for radiation therapy; however, their implementation into high dose rate brachytherapy (HDR-BT) remains underexplored. Surface functionalization with polyethylene glycol (PEG) or integrin-binding domain RGD impacts their biodistribution and intracellular uptake, but whether active cellular targeting via RGD improves radiosensitization for HDR-BT has not been established in vivo. Methods: Here, we systematically compare the radiosensitization efficacy of non-targeted PEGylated GNPs versus actively targeted PEG-RGD GNPs on PC3 prostate cancer cells in vitro and in vivo, using clinically plausible concentrations, dosing procedures, and purpose-built irradiation platforms. 2-dimensional (2-D) and 3-dimensional (3-D) cell cultures, and male NRG mice were irradiated via a 192-Ir source delivered from a clinical HDR-BT afterloader. In vitro samples were dosed at 10 μg Au/mL and mice were intratumourally injected with 50 μL at 2 mg Au/kg bodyweight. Results: PEGylated GNPs did not elicit any radiosensitization either in 2-D, 3-D, or in vivo. RGD-functionalized GNPs elicited a 17% ( p= 0.001) reduction in survival fraction and 33% ( p =0.005) greater DNA DSBs in 2-D cell cultures, and 57% ( p < 0.0001) reduction in 3-D spheroid growth compared to control samples 14 days post-irradiation. In a pre-clinical mouse xenograft model, tumour volume growth was also significantly reduced by 28% ( p= 0.005) 20 days post-irradiation compared to the irradiated control group, with no observable signs of acute toxicity from radiation delivery or administered GNPs. Conclusion: This research represents the first systematic in vitro and in vivo demonstration of GNP-induced radiosensitization using an HDR-BT source with clinically informed intratumoural delivery. Active cellular targeting with RGD functionalization was found to be a critical determinant of radiosensitization efficacy both in vitro and in vivo. Both GNP formulations demonstrated tolerability at the delivered dosing concentrations, and further research into the clinical deliverability of GNPs for HDR-BT is necessitated. The illustration depicts a process involving mice and the effects of gold nanoparticles and 192-Ir on tumor growth. Initially, a syringe labeled ‘Gold nanoparticles’ is shown injecting the tumour of a tumour-bearing mouse. The mouse is then placed in a radiation device where ‘ 192-Ir’ is used to target the tumour. Following this, two outcomes are illustrated: ‘Growth Inhibition’ with a mouse and a symbol indicating prevention and ‘Tumour progression’ when injected with gold nanoparticles; and a mouse without gold nanoparticle injection, suggesting continued tumour growth. The diagram highlights the experimental setup and potential results of using gold nanoparticles and 192-Ir in tumor treatment in mice.Illustration of gold nanoparticles and 192-Ir effects on tumor growth in mice. Keywords: gold nanoparticles, high dose rate brachytherapy, radiotherapy, radiosensitization
Cecchi et al. (Mon,) studied this question.