Recent preclinical and clinical research have highlighted the improved outcomes of combined radiotherapy and immunotherapy. Hafnium is a metallic element with a high atomic number (Z=72) that could be utilized in cancer treatment as a radio-enhancer for conventional radiotherapy. In this study, we synthesized a hafnium-based metal-organic framework (~90 nm) using terephthalic acid and modified it with DSPE-PEG-Folate (HfMOF-PEG-FA) to target colorectal cancer cells. We evaluated readioenhancement of HfMOF-PEG-FA by demonstrating an increase of irradiation-induced cell death via real-time cell proliferation monitoring and clonogenic assay. We then combined HfMOF-PEG-FA with toll-like receptor 7 agonists (Imiquimod) to increase DNA damage and activate the DNA sensing pathway (cGAS-STING). In colorectal cancer cells, HfMOF-PEG-FA increased the number of DNA double-strand breaks induced by gamma-H2AX foci in the nuclei, as well as radiosensitive apoptosis and necrosis. Furthermore, immunogenic cell death induced by calreticulin surface exposure was significantly increased in HfMOF-PEG-FA treated colorectal cancer cells following 2 and 4 Gy irradiation, even after Imiquimod was loaded into HfMOF-PEG-FA. We measured the expressed gene level of a secreted embryonic alkaline phosphatase (SEAP) in human colorectal cancer cells to demonstrate the feasibility of HfMOF-PEG-FA as an immunotherapeutic carrier. Human colorectal cells administrated with Imiquimod loaded HfMOF-PEG-FA significantly promoted the interferon regulatory factor (IRF) pathway, which is downstream of anti-cancer STING and TLR signaling. Finally, we investigated STING-mediated immunity in a CT26 tumor mouse model by profiling T cell infiltration.

Surface functionalized hafnium metal-organic frameworks for the STING pathway activation to promote antitumor immunity

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.