Abstract 4483: Photodynamic therapy in breast cancer by photosensitizer-chitosan particles inducing ferroptosis

Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with poor prognosis and limited treatment options. While chemotherapy has traditionally been the main treatment, resistance frequently emerges, reducing its effectiveness. Recently, a range of immunotherapy strategies, including combinations of chemotherapy and immunotherapy, have expanded treatment possibilities. To further enhance the therapeutic efficacy, there is a desire to combine chemotherapy with other currently used modalities such as photodynamic therapy (PDT) or to encapsulate drugs into nanoparticles (NPs). Ferroptosis has been described as a highly immunogenic type of cell death, characterized by increased ROS and lipid peroxidation. Mesenchymal cancer cells have been reported to be more sensitive to ferroptosis than epithelial cells. We have previously shown that tetraphenylchlorin-conjugated chitosan nanoparticles (TPC-CS NPs) loaded with mertansine and cabazitaxel induce ferroptosis in TNBC.1 In this project, we investigated the effect of TPC-CS NPs together with free RSL3, a ferroptosis inducer. We show that such treatment induces cell death in a mesenchymal breast cancer cell line but not in an epithelial one. The combined treatment also significantly affects lipid peroxidation and mitochondrial function. Based on these results, we encapsulated RSL3 into TPC-CS NPs and used them in two different breast cancer cell lines. We explored the photodynamic effect of empty and RSL3 loaded TPC-CS NPs upon illumination on cell viability by using an MTS assay. Since we have not observed any beneficial effect of TPC-CS NPs-RSL3, we explored the uptake of only empty TPC-CS NPs by using fluorescence microscopy and flow cytometry in these two cell lines. Currently, a biodistribution study in immunocompetent animals bearing 4T1 tumors is being performed. We will perform the maximum tolerable dose experiments for illumination to determine the light dose for further experiments. Moreover, we will perform efficacy studies of TPC-CS NPs and investigate the immune cell composition of tumors and tumor microenvironment using a flow cytometry panel of 25 markers. 1.Pandya AD, Øverbye A, Sahariah P, et al. Drug-Loaded Photosensitizer-Chitosan Nanoparticles for Combinatorial Chemo- and Photodynamic-Therapy of Cancer. Biomacromolecules. 2020/04/13 2020;21(4):1489-1498. This project has received funding from the Europe Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement 956544. Citation Format: Marek Feith, Abhilash D. Pandya, Astrid Hyldbakk, Anders Høgset, Kirsten Sandvig, Tore Skotland, Tore-Geir Iversen, Gunhild Mari Mælandsmo. Photodynamic therapy in breast cancer by photosensitizer-chitosan particles inducing ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4483.