Abstract C147: Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy

The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and gold nanoparticles (GNPs) have established themselves as potent radiosensitizer to significantly enhance Radiotherapy (RT) treatment. The understanding of the biochemical pathways accompanying GNPs radiation amplification can provide information on the molecular pathways relevant to therapeutic efficacy and thus will pave the way for designing novel therapeutic platforms by targeting these pathways. However, there are significant limitations in the ability to deliver sufficiently potent concentration of GNPs to tumor cells and currently there is very limited understanding of the biology of the radiosensitization using GNPs. Thus, to improve the efficacy of radiosensitization and subsequently study the impact of radiosensitization on biochemical pathways, we have fabricated a new generation of targeted GNPs formulation. These ultrasmall 2-3 nm gold nanoparticles were functionalized with hetero-bifunctional PEG, imaging agent- AlexaFlour 647 and targeting peptide- RGD. The in vitro studies showed a robust uptake of these GNPs in different cancer cells lines and clonogenic survival assays have demonstrated a 2.8-fold cell kill enhancement with X-rays in HeLa cell line. To evaluate that these GNPs are targeted to the tumor site, we have injected these nanoparticles via different routes in two different tumor animal models and studied the uptake using in vivo optical imaging. The imaging studies showed highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model injected intravenously with RGD targeted GNPs. The administration of same RGD targeted GNPs formulation via inhalation/instillation (INH) route as opposed to customary intravenous (i.v) route was studied in transgenic lung cancer mice model. Fluorescence imaging and ex-vivo electron microcopy results showed a significantly higher concentration of GNPs (4.7 times) in the lung tumors of mice when using INH delivery compared to i.v. approach. Further, to understand the radiobiology of GNPs in vitro, we have studied the protein expression of γH2aX and RAD51 using western blots. The studies involving the radiation induced alterations in presence of GNPs to study the impact on cell cycle and DNA damage/repair are currently underway. The studies will help identify the specific pathways that are critical to GNP radiotherapy which can be targeted subsequently to further boost the efficacy of GNP radiotherapy. This work is supported by ARMY/ W81XWH-12-1-0154, NSF DGE 0965843, HHS/5U54CA151881-02, NCI R03CA164645, NCI1 K01CA17247801, the Electronics Materials Research Institute at Northeastern University, and Brigham and Women9s Hospital. Citation Format: Rajiv Kumar, Jodi Belz, Ilanchezhian Shanmugam, Wilfred Ngwa, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Radiosensitization using gold nanoparticles for effectively targeting molecular pathways in cancer radiation therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C147.