在本篇研究中，我們合成四氧化三鐵@中空碳球@二氧化矽(Fe 3 O 4 @Hollow Carbon Nanosphere(HCS)@SiO 2 )的中空核殼結構應用於磁吸標定癌細胞並且以近紅外光 (NIR) 808 nm 光激發後產生熱而殺死人類子宮頸癌細胞(Hela cell)。在此，我們合成中空奈米球材料是利用弱酸-鹼的作用力(-COO-/-NH4+/-COO-)形成乳化層將分散好的四氧化三鐵 (約 20 nm) 水包油包覆住，合成四氧化三鐵@聚合中空球 (Fe 3 O 4 @hollow polymer nanosphere (HPS))，約 138 nm，殼層厚度約 22 nm。因使其擁有較好的分散性及可修飾性，以四乙氧基矽烷 (TEOS) 以水解-縮合反應修飾上二氧化矽，此有修飾二氧化矽(厚度約 6 nm) 的材料進入接下來高溫鍛燒的步驟時，可增加材料的強韌度，不會因為高溫碳化完後 HPS 轉成 HCS，因殼層韌度不夠而破損或聚集。高溫鍛燒650 °C 氬 氣 環 境 下 ， 高 溫 下 聚 合 物 進 行 熱 裂 解 (Pyrolysis) 掉 出 許 多 官 能 基 得 到Fe 3 O 4 @HCS@SiO 2 ，大小約 113 nm，厚度約 18 nm。為了增加生物相容性，因此我們
在表面修飾上 3-氨基丙基三乙氧基矽烷 (APTES)帶有-NH 2 的官能基再以 EDC/NHS 反應 形 成 胺 基 的 方 式 接 上 PEG(NH 2 -PEG-COOH) ， 得 到 最 後 的 產 物 。 利 用 此Fe 3 O 4 @HCS@SiO 2 100 ppm (conc. of iron)在紅外光 808 nm (0.8 W /cm2)照射 10 min 溫度可達 60 °C，可知此材料確實有光熱治療效果。MTT 細胞毒性測試結果顯示，材料對細胞並沒有太高的毒性。接著以光熱治療+磁吸的 MTT 得到良好殺死癌細胞的效果。由 AM /PI 染色實驗也可以證實此材料可良好的應用在光熱治療+磁吸的協同治療上。

We synthesize yolk-shell nanoparticle that attracted us to study, for the advantage of their capacity of loading components for further application. Here we load Fe 3 O 4 for magnetic targeting. The carbon shell is used for photothermal therapy. The Fe 3 O 4 @carbon hollow nanospheres modified by PEG on the surface to improve the biocompatibility. In in vitro test, HeLa cell were treated by particles and evaluated
survival rate by MTT assay, results showed low toxic to cell. Combined magnetic targeting and photothermal therapy of the particle treatment we can successfully kill the cancer cell.

(1) Fuertes, A. B.; Sevilla, M.; Valdes-Solis, T.; Tartaj, P. Synthetic route to nanocomposites made up of inorganic nanoparticles confined within a hollow
mesoporous carbon shell. Chem. Mater. 2007, 19, 5418-5423.
(2) Wang, H.; Shen, J.; Li, Y.; Wei, Z.; Cao, G.; Gai, Z.; Hong, K.; Banerjee, P.; Zhou, S. Magnetic iron oxide-fluorescent carbon dots integrated nanoparticles for
dual-modal imaging, near-infrared light-responsive drug carrier and photothermal therapy. Biomaterials Science 2014, 2, 915-923.
(3) Wang, H.; Sun, Y.; Yi, J.; Fu, J.; Di, J.; Alonso, A. d. C.; Zhou, S. Fluorescent porous carbon nanocapsules for two-photon imaging, NIR/pH dual-responsive drug carrier, and photothermal therapy. Biomaterials 2015, 53, 117-126.
(4) Kim, M.; Sohn, K.; Bin Na, H.; Hyeon, T. Synthesis of nanorattles composed of gold nanoparticles encapsulated in mesoporous carbon and polymer shells. Nano Letters 2002, 2, 1383-1387.
(5) Wang, H.; Cao, G.; Gai, Z.; Hong, K.; Banerjee, P.; Zhou, S. Magnetic/NIR-responsive drug carrier, multicolor cell imaging, and enhanced
photothermal therapy of gold capped magnetite-fluorescent carbon hybrid nanoparticles. Nanoscale 2015, 7, 7885-7895.
(6) Huang, C. C.; Chuang, K. Y.; Chou, C. P.; Wu, M. T.; Sheu, H. S.; Shieh, D. B.; Tsai, C. Y.; Su, C. H.; Lei, H. Y.; Yeh, C. S. Size-control synthesis of structure deficient truncated octahedral Fe 3-δ O 4 nanoparticles: high magnetization magnetites as effective hepatic contrast agents. J. Mater. Chem. 2011, 21, 7472-7479.
(7) Wang, G.-H.; Sun, Q.; Zhang, R.; Li, W.-C.; Zhang, X.-Q.; Lu, A.-H. Weak acid-base interaction induced assembly for the synthesis of diverse hollow nanospheres. Chem. Mater. 2011, 23, 4537-4542.
(8) Zhi, M.; Xiang, C.; Li, J.; Li, M.; Wu, N. Nanostructured carbon-metal oxide composite electrodes for supercapacitors: a review. Nanoscale 2013, 5, 72-88.
(9) Chen, Y.; Xu, P.; Shu, Z.; Wu, M.; Wang, L.; Zhang, S.; Zheng, Y.; Chen, H.; Wang, J.; Li, Y.; Shi, J. Multifunctional graphene oxide-based triple stimuli-responsive nanotheranostics. Adv. Func. Mater. 2014, 24, 4386-4396.
(10) Liu, Z.; Fan, A. C.; Rakhra, K.; Sherlock, S.; Goodwin, A.; Chen, X.; Yang, Q.; Felsher, D. W.; Dai, H. Supramolecular stacking of doxorubicin on carbon
nanotubes for in vivo cancer therapy. Angew. Chem. Inter. Edit. 2009, 48, 7668-7672.
(11) Liu, Z.; Robinson, J. T.; Sun, X.; Dai, H. PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. J. Am. Chem. Soc. 2008, 130, 58
10876-10877.
(12) Zhang, L.; Xia, J.; Zhao, Q.; Liu, L.; Zhang, Z. Functional graphene oxide as a nanocarrier for controlled loading and targeted delivery of mixed anticancer drugs.
Small 2010, 6, 537-544.
(13) Baker, S. N.; Baker, G. A. Luminescent carbon nanodots: Emergent nanolights. Angew. Chem. Inter. Ed. 2010, 49, 6726-6744.
(14) Kong, L.; Lu, X.; Bian, X.; Zhang, W.; Wang, C. Constructing carbon-coated Fe 3 O 4 microspheres as antiacid and magnetic support for palladium nanoparticles for catalytic applications. Acs Appl. Mater. Interfaces 2011, 3, 35–42.
(15) Yang, W.; Ratinac, K. R.; Ringer, S. P.; Thordarson, P.; Gooding, J. J.; Braet, F. Carbon nanomaterials in biosensors: Should you use nanotubes or graphene? Angew.
Chem. Int. Ed. 2010, 49, 2114 – 2138.
(16) He, Q.; Ma, M.; Wei, C.; Shi, J. Mesoporous carbon@silicon-silica nanotheranostics for synchronous delivery of insoluble drugs and luminescence
imaging. Biomaterials 2012, 33, 4392-4402.
(17) Wang, Y.; Wang, K.; Zhang, R.; Liu, X.; Yan, X.; Wang, J.; Wagner, E.; Huang, R. Synthesis of core-shell graphitic carbon@silica nanospheres with dual-ordered
mesopores for cancer-targeted photothermochemotherapy. Acs Nano 2014, 8, 7870-7879.
(18) Zhang, S.; Qian, X.; Zhang, L.; Peng, W.; Chen, Y. Composition-property relationships in multifunctional hollow mesoporous carbon nanosystems for pH-responsive magnetic resonance imaging and on-demand drug release. Nanoscale 2015, 7, 7632-7643.
(19) Liang, C. D.; Li, Z. J.; Dai, S. Mesoporous carbon materials: Synthesis and modification. Angew. Chem. Int. Ed. 2008, 47, 3696-3717.
(20) Enzel, P.; Bein, T. Poly(acrylonitrile) chains in zeolite channels - polymerization and pyrolysis. Chem. Mater. 1992, 4, 819-824.
(21) Kyotani, T.; Tsai, L. F.; Tomita, A.Preparation of ultrafine carbon tubes in nanochannels of an anodic aluminum oxide film. Chem. Mater. 1996, 8, 2109-2113.
(22) Zakhidov, A. A.; Baughman, R. H.; Iqbal, Z.; Cui, C. X.; Khayrullin, I.; Dantas, S. O.; Marti, I.; Ralchenko, V. G. Carbon structures with three-dimensional periodicity at optical wavelengths. Science 1998, 282, 897-901.
(23) Yoon, S. B.; Sohn, K.; Kim, J. Y.; Shin, C. H.; Yu, J. S.; Hyeon, T. Fabrication of carbon capsules with hollow macroporous core/mesoporous shell structures. Adv.
Mater. 2002, 14, 19-21.
(24) Carter, J. S.; Kramer, S.; Talley, J. J.; Penning, T.; Collins, P.; Graneto, M. J.; Seibert, K.; Koboldt, C. M.; Masferrer, J.; Zweifel, B. Synthesis and activity of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxygenase-2
inhibitors. Bioorg. Med. Chem. Lett. 1999, 9, 1171-1174.
(25) Kosonen, H.; Valkama, S.; Nykänen, A.; Toivanen, M.; Brinke, G. t.; Ruokolainen, J.; Ikkala, O. Functional porous structures based on the pyrolysis of
cured templates of block copolymer and phenolic resin. Adv. Mater. 2006, 18, 201-205.
(26) Meng, Y.; Gu, D.; Zhang, F.; Shi, Y.; Cheng, L.; Feng, D.; Wu, Z.; Chen, Z.; Wan, Y.; Stein, A.; Zhao, D. A family of highly ordered mesoporous polymer resin
and carbon structures from organic-organic self-assembly. Chem. Mater. 2006, 18, 4447-4464.
(27) Meng, Y.; Gu, D.; Zhang, F. Q.; Shi, Y. F.; Yang, H. F.; Li, Z.; Yu, C. Z.; Tu, B.; Zhao, D. Y. Ordered mesoporous polymers and homologous carbon frameworks:
Amphiphilic surfactant templating and direct transformation. Angew. Chem. Inter. Edit. 2005, 44, 7053-7059.
(28) Tanaka, S.; Nishiyama, N.; Egashira, Y.; Ueyama, K. Synthesis of ordered mesoporous carbons with channel structure from an organic-organic nanocomposite. Chem. Comm. 2005, 2125-2127.
(29) Valkama, S.; Nykanen, A.; Kosonen, H.; Ramani, R.; Tuomisto, F.; Engelhardt, P.; ten Brinke, G.; Ikkala, O.; Ruokolainen, J. Hierarchical porosity in
self-assemhled polymers: Post-modification of block copolymer-phenolic resin complexes hy pyrolysis allows the control of micro- and mesoporosity. Adv. Func. Mater. 2007, 17, 183-190.
(30) Zhang, F.; Meng, Y.; Gu, D.; Yan, Y.; Chen, Z.; Tu, B.; Zhao, D. An aqueous cooperative assembly route to synthesize ordered mesoporous carbons with controlled structures and morphology. Chem. Mater. 2006, 18, 5279-5288.
(31) Liang, C. D.; Hong, K. L.; Guiochon, G. A.; Mays, J. W.; Dai, S. Synthesis of a large-scale highly ordered porous carbon film by self-assembly of block copolymers.
Angew. Chem. Inter. Edi. 2004, 43, 5785-5789.
(32)Brodie, B. C. On the atomic weight of graphite. Phil. Trans. R. Soc. Lond. 1859, 149, 249-259.
(33) Liu, H.; Lv, T.; Zhu, Z. Template-assisted synthesis of hollow TiO 2 @rGO core-shell structural nanospheres with enhanced photocatalytic activity. J. Mol. Cata. A-Chem. 2015, 404, 178-185.
(34) Kim, Y. K.; Na, H. K.; Kim, S.; Jang, H.; Chang, S. J.; Min, D. H. One-Pot Synthesis of multifunctional Au@Graphene oxide nanocolloid Core@Shell nanoparticles for raman bioimaging, photothermal, and photodynamic therapy. Small 2015, 11, 2527-2535.
(35) Cao, L.; Wang, X.; Meziani, M. J.; Lu, F. S.; Wang, H. F.; Luo, P. J. G.; Lin, Y.; Harruff, B. A.; Veca, L. M.; Murray, D.; Xie, S. Y.; Sun, Y. P. Carbon dots for multiphoton bioimaging. J. Am. Chem. Soc. 2007, 129, 11318-11319.
(36) Hu, L.; Sun, Y.; Li, S.; Wang, X.; Hu, K.; Wang, L.; Liang, X.; Wu, Y. Multifunctional carbon dots with high quantum yield for imaging and gene delivery. Carbon 2014, 67, 508-513.
(37) Cao, L.; Sahu, S.; Anilkumar, P.; Bunker, C. E.; Xu, J.; Fernando, K. A. S.; Wang, P.; Guliants, E. A.; Tackett, K. N.; Sun, Y.-P. Carbon nanoparticles as
visible-light photocatalysts for efficient CO2 conversion and beyond. J. Am. Chem. Soc. 2011, 133, 4754-4757.
(38) Wang, L.; Sun, Q.; Wang, X.; Wen, T.; Yin, J. J.; Wang, P.; Bai, R.; Zhang, X. Q.; Zhang, L. H.; Lu, A. H.; Chen, C. Using hollow carbon nanospheres as a
light-induced free radical generator to overcome chemotherapy resistance. J. Am. Chem. Soc. 2015, 137, 1947-1955.
(39) Xiaohua Huanga; El-Sayed, M. A. Plasmonic photo-thermal therapy (PPTT). Alexandria J. Med. 2011, 47, 1-9.
(40) Smith, A. M.; Mancini, M. C.; Nie, S. Second window for in vivo imaging. Nature Nanotechnology. 2009, 710-711.
(41) Brunetaud, J. M.; Mordon, S.; Maunoury, V.; Beacco, C. Non-PDT uses of lasers in oncology. Lasers in Medical Sci. 1995, 10, 3-8.
(42) Link, S.; Ei-Sayed, M. A. Optical properties and ultrafast dynamics of metallic nanocrystals. Annu. Rev. Phys. Chem. 2003, 54, 331-366.
(43) Pustovalov, V. K.; Smetannikov, A. S.; Zharov, V. P. Photothermal and accompanied phenomena of selective nanophotothermolysis with gold nanoparticles
and laser pulses. Laser Phys. Lett. 2008, 5, 775-792.
(44) Martin, S. J.; Henry, C. M.; Cullen, S. P. A Perspective on mammalian caspases as positive and negative regulators of inflammation. Molecular Cell 2012, 46, 387-397.
(45) Melamed, J. R.; Edelstein, R. S.; Day, E. S. Elucidating the fundamental mechanisms of cell death triggered by thotothermal therapy. Acs Nano 2015, 9, 6-11.
(46) Cai, X.; Jia, X.; Gao, W.; Zhang, K.; Ma, M.; Wang, S.; Zheng, Y.; Shi, J.; Chen, H. A versatile nanotheranostic agent for efficient dual-mode imaging guided synergistic chemo-thermal tumor therapy. Adv. Func. Mater. 2015, 25, 2520-2529.
(47) Chen, Q.; Wang, C.; Zhan, Z. X.; He, W. W.; Cheng, Z. P.; Li, Y. Y.; Liu, Z. Near-infrared dye bound albumin with separated imaging and therapy wavelength channels for imaging-guided photothermal therapy. Biomaterials 2014, 35, 8206-8214.
(48) Hu, K. W.; Jhang, F. Y.; Su, C. H.; Yeh, C. S. Fabrication of Gd 2 O(CO 3 ) 2 center dot H 2 O/silica/gold hybrid particles as a bifunctional agent for MR imaging and photothermal destruction of cancer cells. J. Mater. Chem. 2009, 19, 2147-2153.
(49) Su, S.; Ding, Y.; Li, Y.; Wu, Y.; Nie, G. Integration of photothermal therapy and synergistic chemotherapy by a porphyrin self-assembled micelle confers chemosensitivity in triple-negative breast cancer. Biomaterials 2016, 80, 169-178.
(50)Wang, Y.; Yang, T.; Ke, H.; Zhu, A.; Wang, Y.; Wang, J.; Shen, J.; Liu, G.; Chen, C.; Zhao, Y.; Chen, H. Smart albumin-biomineralized nanocomposites for
multimodal imaging and photothermal tumor ablation. Adv. Mater. 2015, 27, 3874-3882.
(51) Yi, X.; Yang, K.; Liang, C.; Zhong, X.; Ning, P.; Song, G.; Wang, D.; Ge, C.; Chen, C.; Chai, Z.; Liu, Z. Imaging-guided combined photothermal and radiotherapy to treat subcutaneous and metastatic tumors using iodine-131-doped copper sulfide nanoparticles. Adv. Func. Mater. 2015, 25, 4689-4699.
(52) Zhou, M.; Zhao, J.; Tian, M.; Song, S.; Zhang, R.; Gupta, S.; Tan, D.; Shen, H.; Ferrari, M.; Li, C. Radio-photothermal therapy mediated by a single compartment
nanoplatform depletes tumor initiating cells and reduces lung metastasis in the orthotopic 4T1 breast tumor model. Nanoscale 2015, 7, 19438-19447.
(53) Wu, Z. C.; Li, W. P.; Luo, C. H.; Su, C. H.; Yeh, C. S. Rattle-type Fe 3 O 4 @CuS developed to conduct magnetically guided photoinduced hyperthermia at first and
second NIR biological windows. Adv. Func. Mater. 2015, 25, 6527-6537.
(54) Cheng, F. Y.; Su, C. H.; Wu, P. C.; Yeh, C. S. Multifunctional polymeric nanoparticles for combined chemotherapeutic and near-infrared photothermal
cancer therapy in vitro and in vivo. Chem. Comm. 2010, 46, 3167-3169.
(55) Kuo, W. S.; Chang, C. N.; Chang, Y. T.; Yang, M. H.; Chien, Y. H.; Chen, S. J.; Yeh, C. S. Gold nanorods in photodynamic therapy, as hyperthermia agents, and in
near-infrared optical imaging. Angew. Chem. Int. Ed. 2010, 49, 2711-2715.
(56) Tsai, M. F.; Chang, S. H. G.; Cheng, F. Y.;Shanmugam, V.; Cheng, Y. S.; Su, C. H.; Yeh, C. S. Au nanorod design as light-absorber in the first and second biological
near-infrared windows for in vivo photothermal therapy. Acs Nano 2013, 7, 5330-5342.
(57) Pitsillides, C. M.; Joe, E. K.; Wei, X. B.; Anderson, R. R.; Lin, C. P. Selective cell targeting with light-absorbing microparticles and nanoparticles. Biophysical
Journal 2003, 84, 4023-4032.
(58) Zhang, Z. J.; Wang, J.; Nie, X.; Wen, T.; Ji, Y.; Wu, X.; Zhao, Y.; Chen, C. Near Infrared Laser-Induced Targeted Cancer Therapy Using Thermoresponsive Polymer
Encapsulated Gold Nanorods. J. Am. Chem. Soc. 2014, 136, 7317-7326.
(59) Chen, Y. W.; Su, Y. L.; Hu, S. H.; Chen, S. Y. Functionalized graphene nanocomposites for enhancing photothermal therapy in tumor treatment. Adv. Drug Deli. Rev. 2016, 1-15.
(60) Chen, Y. C.; Huang, X. C.; Luo, Y. L.; Chang, Y. C.; Hsieh, Y. Z.; Hsu, H. Y. Non-metallic nanomaterials in cancer theranostics: a review of silica- and
carbon-based drug delivery systems. Sci. Tec. Adv. Mater. 2013, 14.
(61) Kim, S.; Ryoo, S. R.; Na, H. K.; Kim, Y. K.; Choi, B. S.; Lee, Y.; Kim, D. E.; Min, D.H. Deoxyribozyme-loaded nano-graphene oxide for simultaneous sensing and silencing of the hepatitis C virus gene in liver cells. Chem. Comm. 2013, 49, 8241-8243.
(62) Robinson, J. T.; Tabakman, S. M.; Liang, Y.; Wang, H.; Casalongue, H. S.; Daniel, V.; Dai, H. Ultrasmall Reduced Graphene Oxide with High Near-Infrared
Absorbance for Photothermal Therapy. J. Am. Chem. Soc. 2011, 133, 6825-6831.
(63)Yang, X.; Wang, Y.; Huang, X.; Ma, Y.; Huang, Y.; Yang, R.; Duan, H.; Chen, Y. Multi-functionalized graphene oxide based anticancer drug-carrier with
dual-targeting function and pH-sensitivity. J. Mater. Chem. 2011, 21, 3448-3454.
(64) Wang, Y.; Wang, K.; Zhao, J.; Liu, X.; Bu, J.; Yan, X.; Huang, R. Multifunctional Mesoporous Silica-Coated Graphene Nanosheet Used for Chemo-Photothermal Synergistic Targeted Therapy of Glioma. J. Am. Chem. Soc. 2013, 135, 4799-4804.
(65) Lyer, S.; Singh, R.; Tietze, R.; Alexiou, C. Magnetic nanoparticles for magnetic drug targeting. Biomed. Eng. Biomed. Tech. 2015, 60, 465-475.
(66) Peng, X. H.; Qian, X. M.; Mao, H.; Wang, A. Y.; Chen, Z.; Nie, S. M.; Shin, D. M. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy. Inter. J. Nanomedi. 2008, 3, 311-321.
(67) Rahman, I. A.; Jafarzadeh, M.; Sipaut, C. S.Synthesis of organo-functionalized nanosilica via a co-condensation modification using gamma-aminopropyltriethoxysilane (APTES). Ceram. Inter. 2009, 35, 1883-1888.
(68) Zhang, Z. J.; Narumi, K.; Naramoto, H. Structural change of a hydrogenated carbon film upon heating. J. Phys.:Condens. Matter 2001, 13, L475-L481.
(69) Ferrari, A. C. Raman spectroscopy of graphene and graphite: Disorder, electron-phonon coupling, doping and nonadiabatic effects. Solid State Comm. 2007, 143, 47-57.