2860 - Multifunctional Ruthenium Covalent Organic Framework Sequentially Sensitize Radio-Radio-Dynamic-Immunotherapy against Cancer

Y. Min¹, Q. Li², C. Cheng², and X. Peng¹; ¹West China Hospital, Chengdu, China, ²Sichuan University, Chengdu, China

Purpose/Objective(s): Radiotherapy (RT) is an extensively used strategy for cancer treatment, but its therapeutic effect is usually limited by the abnormal tumor microenvironment (TME). Besides, radiotherapy may induce immunogenic cell death (ICD), thereby triggering the anti-tumor adaptive immune response. However, radiation-induced systemic immune response is insufficient to control tumor metastases and recurrence. Thus, we aim to design a novel nano-enzyme based radiosensitizer to enhance the radio-immunotherapy against cancer. Materials/

Methods: We demonstrate the design, synthesis, and performance of a ruthenium-coordinated organic frame material (HDCOF-Ru) to mimic natural enzymes for simultaneously enhancing the radiotherapy and synergizing immunotherapy. The therapeutic effects of HDCOF-Ru nanoparticles (NPs) were explored both in vitro and in vivo. Multicolor immunofluorescence and flow cytometry were performed to investigate the regulating role of HDCOF-Ru NPs in local and systemic immune microenvironments under X-ray. RNA-seq was further conducted to explore the underlying signaling pathways of HDCOF-Ru NPs induced anti-tumor effects.
Results: A unique type of nanoscale frame coordination polymer, HDCOF-Ru NPs, was fabricated as both a radiosensitizer and an immune adjuvant for enhanced radio-immunotherapy to inhibit cancer progression, metastasis, and recurrence. In the two-dimensional periodicity of HDCOF-Ru NPs, the uniform dispersion of Ru atoms with higher atomic numbers increases the deposition of X-ray, thus promoting the production of free radicals induced by ionizing radiation. Four-toothed double Schiff base position coordinates two Ru atoms as a highly efficient mimics active center, greatly promoting the generation of reactive oxygen species (ROS), assisting ionizing radiation promotes the death of tumor cells. The multifunctional enzyme-like activities can prevent the repair of damaged DNA, relieve the hypoxic immunosuppressive TME, and generate ROS to induce cell apoptosis to sensitize radiotherapy. The RNA-seq analyses determined the HDCOF-Ru NPs could downregulate calcium signaling pathways to inhibit the proliferation and enhance the apoptosis of cancer cells induced by radiotherapy. Moreover, HDCOF-Ru NPs-based RT could strongly inhibit the growth of distant tumors and induce ICD of metastatic cancer cells by recruiting different cytotoxicity immune cells and mediating the pro-inflammation M1 polarization of macrophage and reducing the proportion of CD8⁺ PD-1⁺ cells for synergizing immunotherapy. The HDCOF-Ru NPs presented limited biotoxicity in tumor bearing mice.
Conclusion: The multifunctional novel radiosensitizer HDCOF-Ru NPs may have great potential for future clinical translation to achieve activatable multidimensional radio-immuno-dynamic cancer therapy.