Co-delivery of PARP and PI3K inhibitors by nanoscale metal–organic frameworks for enhanced tumor chemoradiation
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Conroy Sun1,3(
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Due to their complementary activity, the use of DNA damage repair (DDR) inhibitors during radiotherapy (RT) has yielded promising results. Unfortunately, this approach is often hindered by toxicity and poor in vivo stability of the DDR inhibitors. Nanoscale metal-organic frameworks (nMOFs) represent an emerging class of crystalline materials which exhibit advantageous properties over traditional nanomaterials and demonstrate great potential in oncology. Herein, a unique, synergistic treatment strategy for enhancing the therapeutic efficacy of RT via nMOF-mediated drug delivery and RT enhancement was evaluated. A nMOF containing the high-Z element Hf and the ligand 1, 4-dicarboxybenzene (Hf-BDC) was synthesized and loaded with the two DDR inhibitor drugs, talazoparib and buparlisib (TB@Hf-BDC-PEG). TB@Hf-BDC-PEG augmented RT by increasing reactive oxygen species generation and thus DNA damage of which repair was inhibited thereafter. Synergistic enhancement was demonstrated in vivo where the combination of concurrent radiation with intravenous TB@Hf-BDC-PEG administration resulted in improved tumor control and increased apoptosis. Importantly, no apparent toxicity was observed with nMOF treatment, supporting its potential as an attractive candidate over traditional nanomaterials. This work provides the first report of nMOFs employed to enhance the therapeutic response to RT through DDR inhibitor delivery and physical radiation dose enhancement.
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Co-delivery of PARP and PI3K inhibitors by nanoscale metal–organic frameworks for enhanced tumor chemoradiation
), Conroy Sun1,3(
)
Abstract
Due to their complementary activity, the use of DNA damage repair (DDR) inhibitors during radiotherapy (RT) has yielded promising results. Unfortunately, this approach is often hindered by toxicity and poor in vivo stability of the DDR inhibitors. Nanoscale metal-organic frameworks (nMOFs) represent an emerging class of crystalline materials which exhibit advantageous properties over traditional nanomaterials and demonstrate great potential in oncology. Herein, a unique, synergistic treatment strategy for enhancing the therapeutic efficacy of RT via nMOF-mediated drug delivery and RT enhancement was evaluated. A nMOF containing the high-Z element Hf and the ligand 1, 4-dicarboxybenzene (Hf-BDC) was synthesized and loaded with the two DDR inhibitor drugs, talazoparib and buparlisib (TB@Hf-BDC-PEG). TB@Hf-BDC-PEG augmented RT by increasing reactive oxygen species generation and thus DNA damage of which repair was inhibited thereafter. Synergistic enhancement was demonstrated in vivo where the combination of concurrent radiation with intravenous TB@Hf-BDC-PEG administration resulted in improved tumor control and increased apoptosis. Importantly, no apparent toxicity was observed with nMOF treatment, supporting its potential as an attractive candidate over traditional nanomaterials. This work provides the first report of nMOFs employed to enhance the therapeutic response to RT through DDR inhibitor delivery and physical radiation dose enhancement.
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Acknowledgements
This work was supported by the National Institutes of Health NIGMS as a Maximizing Investigators' Research Award, 1R35GM119839-01 and Oregon State University College of Pharmacy Start-up Funds. We thank the Histology Core and the Advanced Light Microscopy Core at Oregon Health and Science University for tissue analysis support. Additionally, we thank the Center for Electron Microscopy and Nanofabrication at Portland State University for electron microscopy support, and the Trace Element Analysis Laboratory at Portland State University for ICPMS support. Lastly, the authors thank Colin Eaton and Kyle Holmes for weighing organs, homogenizing tissue and data entry.
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