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• 12418

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  P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 12425

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    P3.05-007 - Epidermal Growth Factor Receptor Targeted Gold Nanoparticles for the Radiation Treatment of Non-Small Cell Lung Cancer (ID 1480)

    09:30 - 09:30  |  Author(s): A. McEwan
    • Abstract

    Background
    Lung cancer accounts for the greatest cancer related mortality world wide, with two thirds of all patients receiving radiation therapy as part of their cancer care. Despite advancements made, the overall 5-year survival in Canada remains less than 20%. Developments in nanotechnology have proven to possess exciting potential in the treatment of various malignancies. Nanoparticles with high atomic number, such as Gold (GNPs), facilitate surprising local enhancement secondary to gold’s strong photoelectric absorption coefficient. GNPs are capable of forming covalent bonds, enabling the creation of “targeted” radio-sensitizing agents. The goal of this study is to evaluate the in vitro and in vivo radiation potential and biodistribution profile of GNPs targeted against the epidermal growth factor receptor (EGFR) using the monoclonal antibody Cetuximab (GNP-cetuxumab) stabilized with thiolated polyethylene glycol (SH-PEG) for the treatment of non-small cell lung cancer (NSCLC). To date a comprehensive evaluation of such a platform has not been undertaken.

    Methods
    We examined the radiation enhancement of 50nm GNPs in vitro using SKMES-1 (High wild type EGFR expression) and h460 (low wild type EGFR expression) NSCLC cell lines, both possessing Kras mutations. MTS, clonogenic assays and flow cytometry were used to assess radiation effect using 4 groups (no GNPs, GNPs, GNPs bound to SH-PEG stabilizer, GNP-Cetuximab). In vivo biodistribution was conducted on balb-c nude mice bearing two flank subcutaneous SKMES-1 xenografts. One tumor received a single radiation exposure (200 kVp, 8 Gray) prior to tail vein injection of GNP-cetuximab or GNP-PEG in order to assess the effect radiation induced inflammation may have on GNP tumor uptake. Tumors and organs were harvested at various time points with GNP concentration determined using inductively coupled mass spectroscopy. In vivo radiation experiments were conducted on 3 flank tumor bearing groups (each group = 7): 1) radiation only, no nanoparticles 2) GNP-PEG, GNP stabilized by bound PEG and 3) GNP-Cetuximab. Four weekly radiation fractions (4Gy, 200 kVp) with weekly tail vein injection timing based on the biodistribution results were administered. Tumor growth kinetics was then evaluated.

    Results
    Significant in vitro radiation effect was observed in the GNP groups compared to the radiation only group. GNP-cetuximab and GNP-PEG demonstrated enhanced radiation effect as compared to unfunctionalized GNPs. In the biodistribution experiment, the peak intra-tumor concentration without pre-administered radiation in the GNP-PEG group was twice that of the GNP-Cetuximab group 5 days after tail vein injection. Tumor pre-irradiation resulted in a doubling of intra-tumor nanoparticle uptake in both groups. At the end of radiation therapy experiment, the GNP-PEG group demonstrated the greatest reduction in tumor growth as compared to the radiation alone group (52mm[3] vs 180mm[3 ]respectively, p<0.01).

    Conclusion
    Despite the superiority of GNPs bound to cetuximab in vitro as a radiation enhancer, the favorable tumor biodistribution of the GNP-PEG accounted for the most dramatically reduced tumor growth kinetics observed. The future utility of targeted nanoparticles requires further investigation in light of these findings. In this study we demonstrate the exciting in vitro and in vivo potential of GNPs in the radiation treatment of NSCLC.