普魯士藍奈米粒子具有良好的生物相容性以及光熱轉換效率，近年來在生醫材料方面發表了許多關於腫瘤治療及診斷的文獻，但卻鮮少人針對減少腫瘤缺氧區域做相關的研究。我們利用普魯士藍提供光熱效果，並藉由表面修飾上碳酸氫根可釋放二氧化碳之性質，做減少腫瘤缺氧區域之研究。
首先合成普魯士藍奈米粒子，並利用其表面三價鐵離子和碳酸氫根配位，使碳酸氫根修飾於普魯士藍表面，最後修飾上聚乙二醇以增加生物相容性以及材料分散性。接著利用普魯士藍提供光熱效果，使碳酸氫根斷鍵並釋放出二氧化碳，二氧化碳可使腫瘤微環境氧氣含量下降，使腫瘤細胞增加表現HIF-1α，進而造成血管新生，以傳遞更多氧氣至腫瘤缺氧區域，可減少腫瘤缺氧區域。

In this study, we provide a strategy of the metal ion-ligand coordination feature for the Prussian blue nanoparticles showing the capability of CO2 release to reduce hypoxia. we synthesis of Prussian blue nanoparticle and modify the bicarbonate on the Prussian blue surface. Last, we modify the PEG on the Prussian blue surface. The Prussian blue revealing NIR light-induced hyperthermia resulted in the decomposition of bicarbonate into CO2. The CO2 development increased HIF-1a and new blood vessels to reduced hypoxia.

1. Zhu, Q.L. and Q. Xu, Metal-organic framework composites. Chem Soc Rev, 2014. 43(16): p. 5468-512.

2. Zhao, D., et al., Sensing-functional luminescent metal–organic frameworks. CrystEngComm, 2016. 18(21): p. 3746-3759.

3. Chen, H., et al., Facile synthesis of Prussian blue nanoparticles as pH-responsive drug carriers for combined photothermal-chemo treatment of cancer. RSC Adv., 2017. 7(1): p. 248-255.

4. Chen, W., et al., Cell Membrane Camouflaged Hollow Prussian Blue Nanoparticles for Synergistic Photothermal-/Chemotherapy of Cancer. Advanced Functional Materials, 2017. 27(11): p. 1605795.

5. Hu, M., et al., Synthesis of Prussian blue nanoparticles with a hollow interior by controlled chemical etching. Angew Chem Int Ed Engl, 2012. 51(4): p. 984-8.

6. Jing, L., et al., Prussian blue coated gold nanoparticles for simultaneous photoacoustic/CT bimodal imaging and photothermal ablation of cancer. Biomaterials, 2014. 35(22): p. 5814-21.

7. Cai, X., et al., A Versatile Nanotheranostic Agent for Efficient Dual-Mode Imaging Guided Synergistic Chemo-Thermal Tumor Therapy. Advanced Functional Materials, 2015. 25(17): p. 2520-2529.

8. Fu, G., et al., Magnetic Prussian blue nanoparticles for targeted photothermal therapy under magnetic resonance imaging guidance. Bioconjug Chem, 2014. 25(9): p. 1655-63.

9. Fu, G., et al., Prussian blue nanoparticles operate as a new generation of photothermal ablation agents for cancer therapy. Chem Commun (Camb), 2012. 48(94): p. 11567-9.

10. Zhu, W., et al., Mn2+-doped prussian blue nanocubes for bimodal imaging and photothermal therapy with enhanced performance. ACS Appl Mater Interfaces, 2015. 7(21): p. 11575-82.

11. Kingo Itaya, I.U., Nature of Intervalence Charge-Transfer Bands in Prussian Blues. Inorg. Chem., 1986. 25: p. 389-392.

12. Roper, D.K., W. Ahn, and M. Hoepfner, Microscale Heat Transfer Transduced by Surface Plasmon Resonant Gold Nanoparticles. J Phys Chem C Nanomater Interfaces, 2007. 111(9): p. 3636-3641.

13. Li, W.P., et al., Controllable CO Release Following Near-Infrared Light-Induced Cleavage of Iron Carbonyl Derivatized Prussian Blue Nanoparticles for CO-Assisted Synergistic Treatment. ACS Nano, 2016. 10(12): p. 11027-11036.

14. Jia, X., et al., Perfluoropentane-encapsulated hollow mesoporous prussian blue nanocubes for activated ultrasound imaging and photothermal therapy of cancer. ACS Appl Mater Interfaces, 2015. 7(8): p. 4579-88.

15. Brown, J.M. and W.R. Wilson, Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer, 2004. 4(6): p. 437-47.

16. Luo, C.H., et al., Bacteria-Mediated Hypoxia-Specific Delivery of Nanoparticles for Tumors Imaging and Therapy. Nano Lett, 2016. 16(6): p. 3493-9.

17. Song, X., et al., Ultrasound Triggered Tumor Oxygenation with Oxygen-Shuttle Nanoperfluorocarbon to Overcome Hypoxia-Associated Resistance in Cancer Therapies. Nano Lett, 2016. 16(10): p. 6145-6153.

18. Xia, Y., H.K. Choi, and K. Lee, Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur J Med Chem, 2012. 49: p. 24-40.

19. Cheng, Y., et al., Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy. Nat Commun, 2015. 6: p. 8785.

20. Gordijo, C.R., et al., Design of Hybrid MnO2-Polymer-Lipid Nanoparticles with Tunable Oxygen Generation Rates and Tumor Accumulation for Cancer Treatment. Advanced Functional Materials, 2015. 25(12): p. 1858-1872.

21. Fan, W., et al., Intelligent MnO2 Nanosheets Anchored with Upconversion Nanoprobes for Concurrent pH-/H2O2-Responsive UCL Imaging and Oxygen-Elevated Synergetic Therapy. Adv Mater, 2015. 27(28): p. 4155-61.

22. Chen, Q., et al., Intelligent Albumin-MnO2 Nanoparticles as pH-/H2 O2 -Responsive Dissociable Nanocarriers to Modulate Tumor Hypoxia for Effective Combination Therapy. Adv Mater, 2016. 28(33): p. 7129-36.

23. Cheng, Y., et al., Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy. Nat Commun, 2015. 6: p. 8785.

24. Xu, L., et al., Liposome encapsulated perfluorohexane enhances radiotherapy in mice without additional oxygen supply. J Transl Med, 2016. 14: p. 268.

25. Song, G., et al., Perfluorocarbon-Loaded Hollow Bi2Se3 Nanoparticles for Timely Supply of Oxygen under Near-Infrared Light to Enhance the Radiotherapy of Cancer. Adv Mater, 2016. 28(14): p. 2716-23.

26. Keramaris, N.C., et al., Fracture vascularity and bone healing: A systematic review of the role of VEGF. Injury, 2008. 39: p. S45-S57.

27. Brandi, C., et al., Carbon dioxide therapy in the treatment of localized adiposities: clinical study and histopathological correlations. Aesthetic Plast Surg, 2001. 25(3): p. 170-4.

28. Koga, T., et al., Topical cutaneous CO2 application by means of a novel hydrogel accelerates fracture repair in rats. J Bone Joint Surg Am, 2014. 96(24): p. 2077-84.

29. Li, W.P., et al., CO2 Delivery To Accelerate Incisional Wound Healing Following Single Irradiation of Near-Infrared Lamp on the Coordinated Colloids. ACS Nano, 2017. 11(6): p. 5826-5835.

30. Keramaris, N.C., et al., Fracture vascularity and bone healing: A systematic review of the role of VEGF. Injury, 2008. 39: p. S45-S57.
31. Alan Sandler, M.D., Robert Gray, Ph.D., Michael C. Perry, M.D., Julie Brahmer, M.D.,Joan H. Schiller, M.D., Afshin Dowlati, M.D., Rogerio Lilenbaum, M.D.,and David H. Johnson, M.D., Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell Lung Cancer. The new england journal o f medicine, 2006. 355: p. 2542-2550.

32. Lin, L., et al., Synthesis, characterization and the electrocatalytic application of prussian blue/titanate nanotubes nanocomposite. Solid State Sciences, 2010. 12(10): p. 1764-1769.

33. Li, W.P., et al., CO2 Delivery To Accelerate Incisional Wound Healing Following Single Irradiation of Near-Infrared Lamp on the Coordinated Colloids. ACS Nano, 2017. 11(6): p. 5826-5835.

34. Murdoch, C., A. Giannoudis, and C.E. Lewis, Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood, 2004. 104(8): p. 2224-34.

35. Jessica A. Bertout, S.A.P.a.M.C.S., The impact of O2 availability on human cancer. Nat Rev Cancer., 2008. 8.

36. Lin, L., et al., Synthesis, characterization and the electrocatalytic application of prussian blue/titanate nanotubes nanocomposite. Solid State Sciences, 2010. 12(10): p. 1764-1769.

37. Rajendran, S., et al., Green Electrochemistry - A Versatile Tool in Green Synthesis: an Overview. Portugaliae Electrochimica Acta, 2016. 34(5): p. 321-342.

38. Abdullahi Mohamed Farah, N.D.S., Force Tefo Thema, Johannes Sekomeng Modise and Ezekiel Dixon Dikio, Fabrication of Prussian Blue/Multi-Walled Carbon Nanotubes Modified Glassy Carbon Electrode for Electrochemical Detection of Hydrogen Peroxide. Int. J. Electrochem. Sci., 2012. 7: p. 4302 - 4313.