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.

Critical parameters to translate gold nanoparticles as radiosensitizing agents into the clinic

“…Building on the hard lessons learned from the first two generations third‐generation NPs is being made to give more precise control over biodistribution in vivo and disease‐responsive drug release (Grieneisen & Zhang, 2011; Kumar et al, 2013a). Recent studies show the development of a third‐generation platform for RT applications called the AuRad™ (Kumar et al, 2013a). The multifunctional gold nanorod for RT is made with size and surface functionalization as two of its most important features.…”

“…Furthermore, GNPs have surface features that can be modified and tailored for specific applications, making GNPs the most desirable radiosensitizers for radiotherapy (Boateng & Ngwa, 2020; Cooper et al, 2014). GNPs can be coated with polyethylene glycol (PEG) or complexed with other targeting ligands and drugs for specific targeting purposes (M. Guo et al, 2017; Hainfeld et al, 2008; Kumar et al, 2013b). Studies have illustrated that PEG‐coated GNPs have higher cellular uptake than bare GNPs without any ligands (M. Guo et al, 2017; Kumar et al, 2013).…”

“…GNPs can be coated with polyethylene glycol (PEG) or complexed with other targeting ligands and drugs for specific targeting purposes (M. Guo et al, 2017; Hainfeld et al, 2008; Kumar et al, 2013b). Studies have illustrated that PEG‐coated GNPs have higher cellular uptake than bare GNPs without any ligands (M. Guo et al, 2017; Kumar et al, 2013). Preclinical, in vitro, in vivo studies and Monte Carlo simulations have shown increased dose enhancement effects with high‐Z NPs (Hainfeld et al, 2008; Ngwa et al, 2012).…”

“…Most PEGylated NPs congregate in and around blood vessels in vivo, limiting their uptake by cells. In order to selectively sensitize tumors to ionizing radiation, it is crucial to create and alter the GNP surface (Kumar et al, 2013b; J. Li, Zhang, et al, 2016; Yasui et al, 2014; X.‐D. Zhang et al, 2012).…”

Cytotoxicity Study of Gold Nanoparticles on the Basal-Like Triple-Negative HCC-1937 Breast Cancer Cell Line

“…Gold nanocomposites can also act as radiosensitizer [16] [17] [18] [19] [20] in order to avoid collateral damages induced by the use of radiotherapy. Gold nanoparticles can also be defined as theranostic tools by combining diagnostic and therapeutic actions [21] [22] [23] [24] [25]. The use of gold nanoparticles to try to cure cancer is a very active field of research.…”