TY - JOUR
T1 - Nanoscale Hafnium Metal–Organic Frameworks Enhance Radiotherapeutic Effects by Upregulation of Type I Interferon and TLR7 Expression
AU - Choi, Eunseo
AU - Landry, Madeleine
AU - Pennock, Nathan
AU - Neufeld, Megan
AU - Weinfurter, Katherine
AU - Goforth, Andrea
AU - Walker, Joshua
AU - Sun, Conroy
N1 - Publisher Copyright:
© 2023 Wiley-VCH GmbH.
PY - 2023/5/19
Y1 - 2023/5/19
N2 - Recent preclinical and clinical studies have highlighted the improved outcomes of combination radiotherapy and immunotherapy. Concurrently, the development of high-Z metallic nanoparticles as radiation dose enhancers has been explored to widen the therapeutic window of radiotherapy and potentially enhance immune activation. In this study, folate-modified hafnium-based metal–organic frameworks (HfMOF-PEG-FA) are evaluated in combination with imiquimod, a TLR7 agonist, as a well-defined interferon regulatory factor (IRF) stimulator for local antitumor immunotherapy. The enhancement of radiation dose deposition by HfMOF-PEG-FA and subsequent generation of reactive oxygen species (ROS) deregulates cell proliferation and increases apoptosis. HfMOF-PEG-FA loaded with imiquimod (HfMOF-PEG-FA@IMQ) increases DNA double-strand breaks and cell death, including apoptosis, necrosis, and calreticulin exposure, in response to X-ray irradiation. Treatment with this multipronged therapy promotes IRF stimulation for subsequent interferon production within tumor cells themselves. The novel observation is reported that HfMOF itself increases TLR7 expression, unexpectedly pairing immune agonist and receptor upregulation in a tumor intrinsic manner, and supporting the synergistic effect observed with the γH2AX assay. T-cell analysis of CT26 tumors following intratumoral administration of HfMOF-PEG-FA@IMQ with radiotherapy reveals a promising antitumor response, characterized by an increase in CD8+ and proliferative T cells.
AB - Recent preclinical and clinical studies have highlighted the improved outcomes of combination radiotherapy and immunotherapy. Concurrently, the development of high-Z metallic nanoparticles as radiation dose enhancers has been explored to widen the therapeutic window of radiotherapy and potentially enhance immune activation. In this study, folate-modified hafnium-based metal–organic frameworks (HfMOF-PEG-FA) are evaluated in combination with imiquimod, a TLR7 agonist, as a well-defined interferon regulatory factor (IRF) stimulator for local antitumor immunotherapy. The enhancement of radiation dose deposition by HfMOF-PEG-FA and subsequent generation of reactive oxygen species (ROS) deregulates cell proliferation and increases apoptosis. HfMOF-PEG-FA loaded with imiquimod (HfMOF-PEG-FA@IMQ) increases DNA double-strand breaks and cell death, including apoptosis, necrosis, and calreticulin exposure, in response to X-ray irradiation. Treatment with this multipronged therapy promotes IRF stimulation for subsequent interferon production within tumor cells themselves. The novel observation is reported that HfMOF itself increases TLR7 expression, unexpectedly pairing immune agonist and receptor upregulation in a tumor intrinsic manner, and supporting the synergistic effect observed with the γH2AX assay. T-cell analysis of CT26 tumors following intratumoral administration of HfMOF-PEG-FA@IMQ with radiotherapy reveals a promising antitumor response, characterized by an increase in CD8+ and proliferative T cells.
KW - DNA damage
KW - IRF activation
KW - T-cell proliferation
KW - cell death
KW - folate
KW - imiquimod
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U2 - 10.1002/adhm.202202830
DO - 10.1002/adhm.202202830
M3 - Article
C2 - 36716704
AN - SCOPUS:85148469975
SN - 2192-2640
VL - 12
JO - Advanced Healthcare Materials
JF - Advanced Healthcare Materials
IS - 13
M1 - 2202830
ER -