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Co-delivery of PARP and PI3K inhibitors by nanoscale metal–organic frameworks for enhanced tumor chemoradiation

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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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References

  1. Schaue, D.; McBride, W. H. Opportunities and challenges of radiotherapy for treating cancer. Nat. Rev. Clin. Oncol.2015, 12, 527–540.

    Google Scholar 

  2. Chatterjee, D. K.; Wolfe, T.; Lee, J.; Brown, A. P.; Singh, P. K.; Bhattarai, S. R.; Diagaradjane, P.; Krishnan, S. Convergence of nanotechnology with radiation therapy-insights and implications for clinical translation. Transl. Cancer Res.2013, 2, 256–268.

    CAS  Google Scholar 

  3. He, C. B.; Liu, D. M.; Lin, W. B. Nanomedicine applications of hybrid nanomaterials built from metal-ligand coordination bonds: Nanoscale metal-organic frameworks and nanoscale coordination polymers. Chem. Rev.2015, 115, 11079–11108.

    CAS  Google Scholar 

  4. Steel, G. G.; Peckham, M. J. Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivity. Int. J. Radiat. Oncol. Biol. Phys.1979, 5, 85–91.

    CAS  Google Scholar 

  5. Hartshorn, C. M.; Bradbury, M. S.; Lanza, G. M.; Nel, A. E.; Rao, J. H.; Wang, A. Z.; Wiesner, U. B.; Yang, L.; Grodzinski, P. Nanotechnology strategies to advance outcomes in clinical cancer care. ACS Nano2018, 12, 24–43.

    CAS  Google Scholar 

  6. Furukawa, H.; Cordova, K. E.; O’Keeffe, M.; Yaghi, O. M. The chemistry and applications of metal-organic frameworks. Science2013, 341, 1230444.

    Google Scholar 

  7. Wu, M. X.; Yang, Y. W. Metal-organic framework (MOF)-based drug/cargo delivery and cancer therapy. Adv. Mater.2017, 29, 1606134.

    Google Scholar 

  8. Simon-Yarza, T.; Mielcarek, A.; Couvreur, P.; Serre, C. Nanoparticles of metal-organic frameworks: On the road to in vivo efficacy in biomedicine. Adv. Mater.2018, 30, 1707365.

    Google Scholar 

  9. Liu, J. J.; Yang, Y.; Zhu, W. W.; Yi, X.; Dong, Z. L.; Xu, X. N.; Chen, M. W.; Yang, K.; Lu, G.; Jiang, L. X. et al. Nanoscale metal-organic frameworks for combined photodynamic & radiation therapy in cancer treatment. Biomaterials2016, 97, 1–9.

    CAS  Google Scholar 

  10. Chen, D. Q.; Yang, D. Z.; Dougherty, C. A.; Lu, W. F.; Wu, H. W.; He, X. R.; Cai, T.; van Dort, M. E.; Ross, B. D.; Hong, H. In vivo targeting and positron emission tomography imaging of tumor with intrinsically radioactive metal-organic frameworks nanomaterials. ACS Nano2017, 11, 4315–4327.

    CAS  Google Scholar 

  11. Lu, K. D.; Aung, T.; Guo, N. N.; Weichselbaum, R.; Lin, W. B. Nanoscale metal-organic frameworks for therapeutic, imaging, and sensing applications. Adv. Mater.2018, 30, 1707634.

    Google Scholar 

  12. Lan, G. X.; Ni, K. Y.; Veroneau, S. S.; Song, Y.; Lin, W. B. Nanoscale metal-organic layers for radiotherapy-radiodynamic therapy. J. Am. Chem. Soc.2018, 140, 16971–16975.

    CAS  Google Scholar 

  13. Lu, K. D.; He, C. B.; Guo, N. N.; Chan, C.; Ni, K. Y.; Lan, G. X.; Tang, H. D.; Pelizzari, C.; Fu, Y. X.; Spiotto, M. T. et al. Low-dose X-ray radiotherapy-radiodynamic therapy via nanoscale metal-organic frameworks enhances checkpoint blockade immunotherapy. Nat. Biomed. Eng.2018, 2, 600–610.

    CAS  Google Scholar 

  14. Ni, K. Y.; Lan, G. X.; Veroneau, S. S.; Duan, X. P.; Song, Y.; Lin, W. B. Nanoscale metal-organic frameworks for mitochondria-targeted radiotherapy-radiodynamic therapy. Nat. Commun.2018, 9, 4321.

    Google Scholar 

  15. Her, S.; Jaffray, D. A.; Allen, C. Gold nanoparticles for applications in cancer radiotherapy: Mechanisms and recent advancements. Adv. Drug Del. Rev.2017, 109, 84–101.

    CAS  Google Scholar 

  16. Lázaro, I. A.; Lázaro, S. A.; Forgan, R. S. Enhancing anticancer cytotoxicity through bimodal drug delivery from ultrasmall Zr MOF nanoparticles. Chem. Commun.2018, 54, 2792–2795.

    Google Scholar 

  17. Seiwert, T. Y.; Salama, J. K.; Vokes, E. E. The concurrent chemoradiation paradigm-general principles. Nat. Clin. Pract. Oncol.2007, 4, 86–100.

    CAS  Google Scholar 

  18. Hosoya, N.; Miyagawa, K. Targeting DNA damage response in cancer therapy. Cancer Sci.2014, 105, 370–388.

    CAS  Google Scholar 

  19. Dréan, A.; Lord, C. J.; Ashworth, A. PARP inhibitor combination therapy. Crit. Rev. Oncol. Hematol.2016, 108, 73–85.

    Google Scholar 

  20. Jang, N. Y.; Kim, D. H.; Cho, B. J.; Choi, E. J.; Lee, J. S.; Wu, H. G.; Chie, E. K.; Kim, I. A. Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer. BMC Cancer2015, 15, 89.

    Google Scholar 

  21. Philip, C. A.; Laskov, I.; Beauchamp, M. C.; Marques, M.; Amin, O.; Bitharas, J.; Kessous, R.; Kogan, L.; Baloch, T.; Gotlieb, W. H. et al. Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors. BMC Cancer2017, 17, 638.

    Google Scholar 

  22. Yi, Y. W.; Park, J. S.; Kwak, S. J.; Seong, Y. S. Co-treatment with BEZ235 enhances sensitivity of BRCA1-negative breast cancer cells to olaparib. Anticancer Res.2015, 35, 3829–3838.

    CAS  Google Scholar 

  23. Wang, D.; Li, C.; Zhang, Y.; Wang, M.; Jiang, N.; Xiang, L.; Li, T.; Roberts, T. M.; Zhao, J. J.; Cheng, H. et al. Combined Inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes. Gynecol. Oncol.2016, 142, 548–556.

    CAS  Google Scholar 

  24. Juvekar, A.; Burga, L. N.; Hu, H.; Lunsford, E. P.; Ibrahim, Y. H.; Balmañà, J.; Rajendran, A.; Papa, A.; Spencer, K.; Lyssiotis, C. A. et al. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov.2012, 2, 1048–1063.

    CAS  Google Scholar 

  25. Ibrahim, Y. H.; García-García, C.; Serra, V.; He, L.; Torres-Lockhart, K.; Prat, A.; Anton, P.; Cozar, P.; Guzmán, M.; Grueso, J. et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov.2012, 2, 1036–1047.

    CAS  Google Scholar 

  26. Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: Review of recent advances and business prospects. Acta Pharm. Sin. B2015, 5, 442–453.

    Google Scholar 

  27. DuRoss, A. N.; Neufeld, M. J.; Landry, M. R.; Rosch, J. G.; Eaton, C. T.; Sahay, G.; Thomas, C. R. Jr.; Sun, C. Micellar formulation of talazoparib and buparlisib for enhanced DNA damage in breast cancer chemoradiotherapy. ACS Appl. Mater. Interfaces2019, 11, 12342–12356.

    CAS  Google Scholar 

  28. Schaate, A.; Roy, P.; Godt, A.; Lippke, J.; Waltz, F.; Wiebcke, M.; Behrens, P. Modulated synthesis of Zr-based metal-organic frameworks: From nano to single crystals. Chem.–Eur. J.2011, 17, 6643–6651.

    CAS  Google Scholar 

  29. Morris, W.; Wang, S. Z.; Cho, D.; Auyeung, E.; Li, P.; Farha, O. K.; Mirkin, C. A. Role of modulators in controlling the colloidal stability and polydispersity of the UiO-66 metal-organic framework. ACS Appl. Mater. Interfaces2017, 9, 33413–33418.

    CAS  Google Scholar 

  30. He, T.; Xu, X. B.; Ni, B.; Wang, H. Q.; Long, Y.; Hu, W. P.; Wang, X. Fast and scalable synthesis of uniform zirconium-, hafnium-based metal-organic framework nanocrystals. Nanoscale2017, 9, 19209–19215.

    CAS  Google Scholar 

  31. Cavka, J. H.; Jakobsen, S.; Olsbye, U.; Guillou, N.; Lamberti, C.; Bordiga, S.; Lillerud, K. P. A new zirconium inorganic building brick forming metal organic frameworks with exceptional stability. J. Am. Chem. Soc.2008, 130, 13850–13851.

    Google Scholar 

  32. deKrafft, K. E.; Boyle, W. S.; Burk, L. M.; Zhou, O. Z.; Lin, W. B. Zr- and Hf-based nanoscale metal-organic frameworks as contrast agents for computed tomography. J. Mater. Chem.2012, 22, 18139–18144.

    CAS  Google Scholar 

  33. Che, J.; Okeke, C. I.; Hu, Z. B.; Xu, J. DSPE-PEG: A distinctive component in drug delivery system. Curr. Pharm. Des.2015, 21, 1598–1605.

    CAS  Google Scholar 

  34. Strojan, K.; Leonardi, A.; Bregar, V. B.; Križaj, I.; Svete, J.; Pavlin, M. Dispersion of nanoparticles in different media importantly determines the composition of their protein corona. PLoS One2017, 12, e0169552.

    Google Scholar 

  35. Zhu, X. Y.; Gu, J. L.; Wang, Y.; Li, B.; Li, Y. S.; Zhao, W. R.; Shi, J. L. Inherent anchorages in UiO-66 nanoparticles for efficient capture of alendronate and its mediated release. Chem. Commun.2014, 50, 8779–8782.

    CAS  Google Scholar 

  36. Rojas, S.; Colinet, I.; Cunha, D.; Hidalgo, T.; Salles, F.; Serre, C.; Guillou, N.; Horcajada, P. Toward understanding drug incorporation and delivery from biocompatible metal-organic frameworks in view of cutaneous administration. ACS Omega2018, 3, 2994–3003.

    CAS  Google Scholar 

  37. Cunha, D.; Gaudin, C.; Colinet, I.; Horcajada, P.; Maurin, G.; Serre, C. Rationalization of the entrapping of bioactive molecules into a series of functionalized porous zirconium terephthalate MOFs. J. Mater. Chem. B2013, 1, 1101–1108.

    CAS  Google Scholar 

  38. Cunha, D.; Ben Yahia, M.; Hall, S.; Miller, S. R.; Chevreau, H.; Elkaim, E.; Maurin, G.; Horcajada, P.; Serre, C. Rationale of drug encapsulation and release from biocompatible porous metal-organic frameworks. Chem. Mater.2013, 25, 2767–2776.

    CAS  Google Scholar 

  39. Lan, G. X.; Ni, K. Y.; Lin, W. B. Nanoscale metal-organic frameworks for phototherapy of cancer. Coord. Chem. Rev.2019, 379, 65–81.

    CAS  Google Scholar 

  40. Chen, H. M.; Wang, G. D.; Chuang, Y. J.; Zhen, Z. P.; Chen, X. Y.; Biddinger, P.; Hao, Z. L.; Liu, F.; Shen, B. Z.; Pan, Z. W. et al. Nanoscintillator-mediated X-ray inducible photodynamic therapy for in vivo cancer treatment. Nano Lett.2015, 15, 2249–2256.

    CAS  Google Scholar 

  41. Chou, T. C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res.2010, 70, 440–446.

    CAS  Google Scholar 

  42. Albert, J. M.; Cao, C.; Kim, K. W.; Willey, C. D.; Geng, L.; Xiao, D. K.; Wang, H.; Sandler, A.; Johnson, D. H.; Colevas, A. D. et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin. Cancer Res.2007, 13, 3033–3042.

    CAS  Google Scholar 

  43. Banáth, J. P.; Klokov, D.; MacPhail, S. H.; Banuelos, C. A.; Olive, P. L. Residual γH2AX foci as an indication of lethal DNA lesions. BMC Cancer2010, 10, 4.

    Google Scholar 

  44. Banáth, J. P.; MacPhail, S. H.; Olive, P. L. Radiation sensitivity, H2AX phosphorylation, and kinetics of repair of DNA strand breaks in irradiated cervical cancer cell lines. Cancer Res.2004, 64, 7144–7149.

    Google Scholar 

  45. Klokov, D.; MacPhail, S. M.; Banáth, J. P.; Byrne, J. P.; Olive, P. L. Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays. Radiother. Oncol.2006, 80, 223–229.

    CAS  Google Scholar 

  46. Subiel, A.; Ashmore, R.; Schettino, G. Standards and methodologies for characterizing radiobiological impact of high-Z nanoparticles. Theranostics2016, 6, 1651–1671.

    CAS  Google Scholar 

  47. Zheng, X. H.; Wang, L.; Liu, M.; Lei, P. P.; Liu, F.; Xie, Z. G. Nanoscale mixed-component metal-organic frameworks with photosensitizer spatial-arrangement-dependent photochemistry for multimodal-imaging-guided photothermal therapy. Chem. Mater.2018, 30, 6867–6876.

    CAS  Google Scholar 

  48. Horcajada, P.; Chalati, T.; Serre, C.; Gillet, B.; Sebrie, C.; Baati, T.; Eubank, J. F.; Heurtaux, D.; Clayette, P.; Kreuz, C. et al. Porous metal-organic-framework nanoscale carriers as a potential platform for drug delivery and imaging. Nat. Mater.2010, 9, 172–178.

    CAS  Google Scholar 

  49. Baati, T.; Njim, L.; Neffati, F.; Kerkeni, A.; Bouttemi, M.; Gref, R.; Najjar, M. F.; Zakhama, A.; Couvreur, P.; Serre, C. et al. In depth analysis of the in vivo toxicity of nanoparticles of porous iron(III) metal-organic frameworks. Chem. Sci.2013, 4, 1597–1607.

    CAS  Google Scholar 

  50. Hanahan, D.; Weinberg, R. A. Hallmarks of cancer: The next generation. Cell2011, 144, 646–674.

    CAS  Google Scholar 

  51. Knijnenburg, T. A.; Wang, L. H.; Zimmermann, M. T.; Chambwe, N.; Gao, G. F.; Cherniack, A. D.; Fan, H. H.; Shen, H.; Way, G. P.; Greene, C. S. et al. Genomic and molecular landscape of DNA damage repair deficiency across the cancer genome atlas. Cell Rep.2018, 23, 239–254.e6.

    CAS  Google Scholar 

  52. Pilié, P. G.; Tang, C.; Mills, G. B.; Yap, T. A. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat. Rev. Clin. Oncol.2019, 16, 81–104.

    Google Scholar 

  53. Tangutoori, S.; Baldwin, P.; Sridhar, S. PARP inhibitors: A new era of targeted therapy. Maturitas2015, 81, 5–9.

    CAS  Google Scholar 

  54. Galon, J.; Laé, M.; Thariat, J. O.; Carrere, S.; Papai, Z.; Delannes, M.; Sargos, P.; Rochaix, P.; Mangel, L. C.; Sapi, Z. et al. Hafnium oxide nanoparticle activated by radiation therapy generates an anti-tumor immune response. Int. J. Radit. Oncol.2018, 102, S204–S205.

    Google Scholar 

  55. Maggiorella, L.; Barouch, G.; Devaux, C.; Pottier, A.; Deutsch, E.; Bourhis, J.; Borghi, E.; Levy, L. Nanoscale radiotherapy with hafnium oxide nano-particles. Future Oncol.2012, 8, 1167–1181.

    CAS  Google Scholar 

  56. Ni, K. Y.; Lan, G. X.; Chan, C.; Quigley, B.; Lu, K. D.; Aung, T.; Guo, N. N.; La Riviere, P.; Weichselbaum, R. R.; Lin, W. B. Nanoscale metal-organic frameworks enhance radiotherapy to potentiate checkpoint blockade immunotherapy. Nat. Commun.2018, 9, 2351.

    Google Scholar 

  57. Sadeghi-Naini, A.; Papanicolau, N.; Falou, O.; Zubovits, J.; Dent, R.; Verma, S.; Trudeau, M.; Boileau, J. F.; Spayne, J.; Iradji, S. et al. Quantitative ultrasound evaluation of tumor cell death response in locally advanced breast cancer patients receiving chemotherapy. Clin. Cancer Res.2013, 19, 2163–2174.

    CAS  Google Scholar 

  58. Lee, S. Y.; Ju, M. K.; Jeon, H. M.; Jeong, E. K.; Lee, Y. J.; Kim, C. H.; Park, H. G.; Han, S. I.; Kang, H. S. Regulation of tumor progression by programmed necrosis. Oxid. Med. Cell. Longev.2018, 2018, 3537471.

    Google Scholar 

  59. Hirayama, R.; Ito, A.; Tomita, M.; Tsukada, T.; Yatagai, F.; Noguchi, M.; Matsumoto, Y.; Kase, Y.; Ando, K.; Okayasu, R. et al. Contributions of direct and indirect actions in cell killing by high-LET radiations. Radiat. Res.2009, 171, 212–218.

    CAS  Google Scholar 

  60. Koontz, B. F.; Verhaegen, F.; De Ruysscher, D. Tumour and normal tissue radiobiology in mouse models: How close are mice to mini-humans? Br. J. Radiol.2017, 90, 20160441.

    Google Scholar 

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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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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, Oregon, 97201, USA

    Megan J. Neufeld, Allison N. DuRoss, Madeleine R. Landry & Conroy Sun

  2. Department of Chemistry, Portland State University, 1719 SW 10th Ave, Portland, Oregon, 97201, USA

    Hayden Winter & Andrea M. Goforth

  3. Department of Radiation Medicine, Oregon Health & Science University, 3181 S. W. Sam Jackson Park Rd, Portland, Oregon, 97239, USA

    Conroy Sun

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  1. Megan J. Neufeld
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  2. Allison N. DuRoss
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Correspondence to Megan J. Neufeld or Conroy Sun.

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Neufeld, M.J., DuRoss, A.N., Landry, M.R. et al. Co-delivery of PARP and PI3K inhibitors by nanoscale metal–organic frameworks for enhanced tumor chemoradiation. Nano Res. 12, 3003–3017 (2019). https://doi.org/10.1007/s12274-019-2544-z

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