A Novel Synergetic Combined Modality of Nanotechnology, Chemotherapy, and Radiotherapy for the Treatment of Pancreatic Cancer




Alhussan, Abdulaziz

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Pancreatic cancer is one of the deadliest types of cancer, with a five-year survival rate of less than 8%. Despite the current advances in medicine, innovative treatment options are needed. Nanotechnology offers a novel perspective to treat such deadly cancers through their incorporation into radiotherapy (RT), as radiosensitizers, and chemotherapy, as drug carriers, for the goal of having better therapeutic efficacy and reducing normal tissue toxicity. However, the interaction of nanoparticles (NPs) with major cells of the tumor microenvironment (TME) is yet to be understood. Therefore, our first goal was to shed light on the dynamics of NPs within a TME of pancreatic origin. In addition to cancer cells, normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were examined due to their important yet opposite roles of suppressing tumor growth and promoting tumor growth, respectively. Gold nanoparticles (GNPs) were used as promising radiosensitizers due to their biocompatibility and physical and chemical proprieties. Our in vitro 2D monocultures studies revealed that NFs take up less than 50% of GNPs compared to cancer cells, while CAFs had over 300% increase in GNPs uptake compared to cancer cells. Cancer cells, CAFs, and NFs lost ~ 25% of GNPs 24 h post-dosing. We were able to significantly enhance the uptake and retention using the radiosensitizing drug docetaxel (DTX). GNP uptake was improved by a factor of three in cancer cells and a factor of two in CAFs. Both cell lines were able to retain ~ 70% of GNPs even 72 h post-treatment with DTX. Drawing on these encouraging findings, our second goal was to create a 2D co-culture of CAFs and cancer 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, cells were grown in co-culture with different ratios of CAFs to cancer cells. 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/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. In parallel, our third goal was to explore encapsulating the toxic DTX prodrug in lipid nanoparticles (LNPDTX-P) and how that affect GNP uptake in vitro and in vivo in NRG mice. The results show that LNPDTX-P treated tumor samples have double the amount GNPs compared to control samples in both in vitro and in vivo. Based on the outcomes of the preceding studies, we aimed to evaluate the anti-cancer efficacy of GNPs and LNPDTX-P in combination with RT on a 3D co-culture spheroid model. GNPs/RT and RT/LNPDTX-P showed a significant reduction in the spheroid size of 7% and 33%, respectively, and an increase in DNA DSB damage of 20% for RT/GNPs. However, the combination of the two nanoparticles with RT significantly enhanced the anti-cancer efficacy resulting in a 46% decrease in spheroid size and a 39% increase in DNA DSB. The combination of GNPs and LNPDTX-P with RT showed a synergistic effect due to their radiosensitizing properties improving the therapeutic efficacy of each treatment modality alone even in the more treatment resistant co-culture spheroid model. This triple modality presents a promising approach for enhancing cancer treatment while reducing side effects, and ongoing research in this area holds great promise for improving outcomes for cancer patients.



Gold Nanoparticles, Lipid Nanoparticles, Pancreatic Cancer, Docetaxel, MIA PaCa2, Cancer Associated Fibroblasts, Radiotherapy, In Vitro, In vivo