Published In

Advanced Healthcare Materials

Document Type

Post-Print

Publication Date

1-30-2023

Subjects

Nanoparticles -- Radiology

Abstract

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, we evaluate folate-modified hafnium-based metal-organic frameworks (HfMOF-PEG-FA) 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. We report the novel observation that, HfMOF itself increased TLR7 expression, unexpectedly pairing immune agonist and receptor up-regulation in a tumor intrinsic manner, and supporting the synergistic affect 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.

Rights

Copyright © 1999-2023 John Wiley & Sons, Inc.

DOI

10.1002/adhm.202202830

Persistent Identifier

https://archives.pdx.edu/ds/psu/39310

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