Potential of Gold Nanoparticle in Current Radiotherapy Using a Co-Culture Model of Cancer Cells and Cancer Associated Fibroblast Cells

Abdulaziz Alhussan; Nicholas Palmerley; Julian Smazynski; Joanna Karasinska; Daniel J Renouf; David F Schaeffer; Wayne Beckham; Abraham S Alexander; Devika B Chithrani

doi:10.3390/cancers14153586

Potential of Gold Nanoparticle in Current Radiotherapy Using a Co-Culture Model of Cancer Cells and Cancer Associated Fibroblast Cells

Cancers (Basel). 2022 Jul 22;14(15):3586. doi: 10.3390/cancers14153586.

Authors

Abdulaziz Alhussan¹, Nicholas Palmerley¹, Julian Smazynski², Joanna Karasinska³, Daniel J Renouf³, David F Schaeffer^{3

4}, Wayne Beckham^{1

5}, Abraham S Alexander⁵, Devika B Chithrani^{1

5

6

7

8

9}

Affiliations

¹ Department of Physics and Astronomy, University of Victoria, Victoria, BC V8P 5C2, Canada.
² Deeley Research Centre, British Columbia Cancer-Victoria, Victoria, BC V8R 6V5, Canada.
³ Pancreas Centre BC, Vancouver, BC V5Z 1G1, Canada.
⁴ Department of Pathology & Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 1Z7, Canada.
⁵ Radiation Oncology, British Columbia Cancer-Victoria, Victoria, BC V8R 6V5, Canada.
⁶ Centre for Advanced Materials and Related Technologies, Department of Chemistry, University of Victoria, Victoria, BC V8P 5C2, Canada.
⁷ Centre for Biomedical Research, Department of Biology, University of Victoria, Victoria, BC V8P 5C2, Canada.
⁸ Department of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada.
⁹ Department of Computer Science, Mathematics, Physics and Statistics, Okanagan Campus, University of British Columbia, Kelowna, BC V1V 1V7, Canada.

Abstract

Many cancer therapeutics are tested in vitro using only tumour cells. However, the tumour promoting effect of cancer associated fibroblasts (CAFs) within the tumour microenvironment (TME) is thought to reduce cancer therapeutics' efficacy. We have chosen pancreatic ductal adenocarcinoma (PDAC) as our tumor model. Our goal is to create a co-culture of CAFs and tumour cells to model the interaction between cancer and stromal cells in the TME and allow for better testing of therapeutic combinations. To test the proposed co-culture model, a gold nanoparticle (GNP) mediated-radiation response was used. Cells were grown in co-culture with different ratios of CAFs to cancer cells. MIA PaCa-2 was used as our PDAC cancer cell line. Co-cultured cells were treated with 2 Gy of radiation following GNP incubation. DNA damage and cell proliferation were examined to assess the combined effect of radiation and GNPs. Cancer cells in co-culture exhibited up to a 23% decrease in DNA double strand breaks (DSB) and up to a 35% increase in proliferation compared to monocultures. GNP/Radiotherapy (RT) induced up to a 25% increase in DNA DSBs and up to a 15% decrease in proliferation compared to RT alone in both monocultured and co-cultured cells. The observed resistance in the co-culture system may be attributed to the role of CAFs in supporting cancer cells. Moreover, we were able to reduce the activity of CAFs using GNPs during radiation treatment. Indeed, CAFs internalize a significantly higher number of GNPs, which may have led to the reduction in their activity. One reason experimental therapeutics fail in clinical trials relates to limitations in the pre-clinical models that lack a true representation of the TME. We have demonstrated a co-culture platform to test GNP/RT in a clinically relevant environment.

Keywords: MIA PaCa-2; cancer associated fibroblasts; co-culture; gold nanoparticle; monoculture; nanotechnology; pancreatic cancer; radiosensitization.

Grants and funding

This study was funded by Kuwait Foundation for the Advancement of Sciences (KFAS), a Nanomedicines Innovation Network Strategic Initiative fund (NMIN-SI) from Government of Canada, the John R. Evans Leaders Fund (JELF) from the Canada Foundation for Innovation (CFI) and British Columbia Knowledge Development Fund (BCKDF), the NSERC Discovery grant from the Natural Sciences and Engineering Research Council of Canada (NSERC), and a collaborative health grant from the University of Victoria.