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

SIMPLE SUMMARY: Many cancer therapeutics do not account for the complexity of the tumor microenvironment (TME), which may result in failure when applied clinically. In this paper we utilized a simple tumor model made of two types of pancreatic cancer cells that contribute to the tumor environment, i.e., cancer cells and cancer associated fibroblasts. Herein, radiotherapy along with radiosensitizing gold nanoparticles were used to test the efficacy of a co-culture vs. monoculture model. The results show that the co-culture model exhibited heightened resistance to radiation. Furthermore, we found that the combination of gold radiosensitizers with radiotherapy reduced the radioresistance of the co-culture model compared to radiotherapy alone. This study demonstrates the potential of using nanotherapeutics in targeting the complex tumor microenvironment. 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.