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

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.

Dual enhancement in the radiosensitivity of prostate cancer through nanoparticles and chemotherapeutics

“…This increase in the presence of GNPs could lead to reduced activity of CAFs with radiation treatment. A recent co-culture study of tumor cells and CAFs of pancreatic origin showed reduced activity of CAFs with the treatment of GNP/RT (Alhussan et al 2022 ). This suggests that the addition of DTX would further improve the efficacy of GNP/RT on CAFs, and, therefore, be effective when applied to a proper TME.…”

Methodological and Cellular Factors Affecting the Magnitude of Breast Cancer and Normal Cell Radiosensitization Using Gold Nanoparticles

“…Different parameters in AuNPs generated by radiosensitivity are under investigation. The authors 49 highlighted a new kind of factor associated with the radiosensitization effect such as tumor microenvironment (TME). They observed that cancer-associated fibroblasts (CAFs) enhanced pancreatic cancer cell growth, whereas this type of TME cells incorporated more AuNPs than cancer cells.…”

Nanoscintillator Coating: A Key Parameter That Strongly Impacts Internalization, Biocompatibility, and Therapeutic Efficacy in Pancreatic Cancer Models

“…Several studies ranging from Monte Carlo simulations [15] to in vitro and in vivo studies [16][17][18][19][20][21][22][23] have demonstrated that such NPs could sensitize pancreatic cancer cells to X-rays when NPs made of thorium, [15] titanium, [16,17] manganese, [18] yttrium, [19] cerium, [20] gadolinium, [21] and gold [22,23] were incubated with tumor cells. Various effects were reported to explain this efficacy, including increased production of DNA damage [16,18,21,22] and ROS [16,17,19,20] enhanced apoptosis, [16][17][18][19][20]23] reduced cell proliferation, [17,22] and reduced survival fraction. [16,17,20,21] In vivo studies also demonstrated increased animal survival [17,21] and decreased tumor volumes.…”