Inhalation Instillation Research Articles

Abstract B41: Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy

Abstract The use of nanoparticles with high atomic (Z) number have been known to attenuate X-rays and the unique properties associated with gold nanoparticles makes them as potent radiosensitizers for enhancing Radiotherapy (RT) treatments. The interaction of high Z materials with the X-rays results in photoelectric absorption which leads to generation of photoelectrons. These low energy photoelectrons can deliver lethal energy in the close proximity. The success of cancer radiation therapy relies heavily on the effective delivery of radiation dose to the tumor site sparing the surrounding normal tissues. To overcome the limitations associated with increasing the radiation dose, due to normal tissue toxicities, the feasibility of radiosensitizing the tumor using gold nanoparticles provide a promising alternative. Targeting gold nanoparticles based formulations to the tumor prior to radiation therapy will result in radiation dose enhancement, by generating secondary photoelectrons, locally inside the tumor and thereby minimizing the dose dependent toxicity to non-specific neighboring tissues. Here, we have developed different Gold nanoparticles based formulations to locally radiosensitize the tumor cells in three different cancer models. For targeting pancreatic cancers, we have fabricated a new generation of GNPs formulation which are 3-4 nm in diameter and surface passivated with hetero-bifunctional PEG, fluorophore AlexaFlour 647 and peptide RGD. This formulation showed a 2.8-fold in vitro cell kill enhancement with X-rays, as demonstrated by clonogenic survival assays. In vivo studies confirmed the highly specific tumor uptake in tumor endothelial cells in orthotopic pancreatic tumor mice model. The combined treatment in animals treated with GNPs and radiation (10Gy) showed the maximum endothelial cells damage, as confirmed with confocal imaging of the tumor sections and CD31 immunostaining. For targeting the lung cancer, we have used the same GNPs formulation but adopted a inhalation/instillation (INH) route for administering the nanoparticles in vivo in transgenic lung cancer mice model as opposed to customary intravenous (i.v) route. Fluorescence imaging and ex-vivo electron microcopy results showed a 4.7 times higher concentration of GNPs in the lung tumors of mice when using INH delivery compared to i.v. approach. The survival studies with these animals are currently underway. For using these radiosensitizing nanoparticles in brachytherapy applications, we have incorporated GNPs in modified brachytherapy spacers to enhance radiation dose locally in tumor without any additional surgical intervention. These spacers are normally placed inside the tumor to spatially distribute the radioactive seeds. The incorporation of GNPs in these spacers allowed for enhancing the radiation dose by the GNPs released from the spacers. These spacers have same morphology (5 mm in length and 0.8 mm in diameter) as commercial spacers with additional radiosensitizing properties because of doped GNPs. We have shown the time dependent release of the GNPs as a function of size of GNPs from the spacers into the tumor by optical imaging. We have further incorporated the GNPs based brachytherapy spacer with the immunoadjuvants, anti-CD40 to combine the radiation and immunotherapy in a single platform. The preliminary results indicate that gold nanoparticles based nanoplatform shows promise as a potential theranostic radiosensitizer which allows for combining multiple therapies in a single platform. 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 Women's Hospital. Citation Format: Rajiv Kumar, Wilfred Ngwa, Vinit Joshi, Sijumon Kunjachan, Ross Berbeco, Mike Makrigiorgos, Srinivas Sridhar. Gold nanoparticles based platforms for localized radiosensitization in cancer radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B41.

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

Abstract 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 Women's 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.