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.
In this study, two different conical-shape nano-patterns were fabricated on the 2-inch diameter sapphire wafer in order to improve the efficiency of light-emitting diodes. The conical-shape nano-patterns were fabricated on the sapphire wafer using a nanoimprint technique and dry etching
method. A blue LED structure was grown on the nanoscale-patterned sapphire substrates. The photoluminescence and electroluminescence were measured to confirm the effectiveness of the nano-scale patterns. An improvement in the luminescence efficiency was observed in case that nano-patterned
sapphire substrate was used; a 1.44 times-higher photoluminescence intensity and a 1.5 times-higher electroluminescence intensity were observed, compared to those of the light-emitting diodes structure grown on a conventional flat sapphire wafer.
There is a need for more broadly applicable radiosensitizers independent of disease state and DNA protein repair status. High throughput screens hold potential for identifying new classes of radiosensitizers from libraries of small molecules. Our group has developed an in vitro high throughput screen identifying radiosensitizers using high content imaging. Due to chromatin condensation, G2/M is acknowledged as the most radiosensitive phase of the cell cycle. We therefore dosed 4T1 breast cancer cells with a library of 1430 FDA approved drugs, then using the high content images, assessed ability to stall in G2/M. We initially eliminated drugs with less than 30% viability from consideration to negate toxicity effects on the CCI. With a CCI cutoff of two standard deviations from the mean, we attained a hit rate of 2.8% with 40 hits. The screen identified both known and novel radiosensitizers belonging to previously unidentified classes. This methodology of cell cycle analysis was confirmed by the more classical flow cytometry assay and a selected hit from the screen was assessed for radiosensitizing ability by clonogenic and γH2AX assays, and in vivo studies. Based on the clonogenic survival fractions, the radiation enhancement ratio was found to be >1 at all doses between 2-6 Gy for the selected drug, with the highest values at 4 and 5 Gy of 4.5. Furthermore, we found two 10 µM doses of the novel radiosensitizer paired with two fractions of 2 Gy was sufficient to significantly decrease 4T1 tumor volume growth in BALB/c mice.
Citation Format: Madeleine R. Landry, Allison N. DuRoss, Eunseo Choi, Antony Jozic, Dylan Nelson, Conroy Sun. Novel high-throughput screen in a breast cancer cell line to identify potent radiosensitizers [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-087.
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