Targeted Gold Nanoparticles Enhance Radiation Effects In Pancreatic Tumor Models

Pancreatic cancer is currently the fourth leading cause of cancer mortality in the United States and projected to be second by 2020. Due to the high number of patients presenting with locally advanced unresectable disease, localized therapies have emerged as a critical area of research interest. Tumor targeted gold nanoparticles have been shown to enhance radiosensitization. In these studies, we evaluate the radiosensitization potential of nuclear-targeted gold nanoparticles in pancreatic cancer. Gold nanospheres (AuNSs) were targeted using a nuclear localization sequence (NLS) peptide to enhance the accumulation of the particles inside the nucleus. Cellular and nuclear internalization was assessed using transmission electron microscopy, dark field microscopy and western blot analysis together with inductively coupled mass spectrometry (ICP-MS). In vitro radiosensitization was evaluated in human pancreatic adenocarcinoma cancer cells (Panc-1) using clonogenic cell survival assays with doses ranging from 0 to 6 Gy, respectively with varying types of radiation including: Co-60, 250-kVp X-rays, 6 MeV and protons. DNA double strand break (DSB) formation was evaluated via staining for 53BP-1 and γH2A-X foci. In vivo tumor growth delay studies were done using 250-kVp X-rays. Quantitative assessment of cellular internalization showed similar uptake levels of the non-targeted vs. nuclear-targeted particles in cells but relatively higher cytoplasmic and nuclear gold content of the non-targeted and targeted particles, respectively. Clonogenic cell survival indicated a statistically significant difference (p<0.05) in radiosensitization enhancement factors (REF), calculated at the 10% survival fraction between the treatment groups using different types of radiation. DNA DSB assessment showed statistically significantly increased levels of foci in cells treated with both targeted AuNSs and radiation at 1hr and 24hrs following radiation. Preliminary in vivo studies also showed delayed tumor growth with the combined treatment group of targeted AuNSs and radiation.Abstract 3367AuNS Treatment GroupsREF Calculated at 10% Survival# Foci/cell at 1, 24 hoursCo-60250 kVp200 MeV ProtonγH2A-X53BP-1Non-targeted1.011.021.0856, 3055, 29Nuclear-targeted1.101.351.1275, 4371, 41 Open table in a new tab Our data so far indicates that targeting gold nanoparticles to the nucleus results in the augmentation of radiation effects through increased formation of DNA double strand breaks. These results have set the stage for further studies in vivo, which are currently in progress.