臺灣博碩士論文加值系統

目錄 ............................................................................................................. I
表目錄 ...................................................................................................... VI
圖目錄 ..................................................................................................... VII
摘要 ............................................................................................................. 1
ABSTRACT ................................................................................................ 2
第一章 前言............................................................................................. 3
1.1 研究背景及動機 .................................................................... 3
第二章 文獻回顧 .................................................................................... 5
2.1 肝細胞癌 ................................................................................ 5
2.1.1 肝細胞癌的治療方法 ...................................................... 6
2.2 光動力療法 ............................................................................ 7
2.2.1 光動力療法的起源與發展 .............................................. 7
2.2.2 光動力療法的原理 .......................................................... 9
2.2.3 光動力療法的作用機制 ................................................ 10
2.2.4 光敏劑 ............................................................................ 13
2.3 免疫治療 .............................................................................. 17
2.3.1 免疫治療的起源與發展 ................................................ 17
2.3.2 免疫治療的作用機制 .................................................... 19
2.3.3 免疫療法對肝細胞癌的應用 ........................................ 22
2.3.4 奈米粒子用於腫瘤免疫治療 ........................................ 24
2.4 分子拓印技術 ...................................................................... 29
2.4.1 分子拓印技術的起源與發展 ........................................ 29
2.4.2 分子模板的原理 ............................................................ 31
2.4.3 分子模板的應用 ............................................................ 32
2.4.4 蛋白質拓印 .................................................................... 33
2.5 聚乙烯乙烯醇 ...................................................................... 34
2.5.1 聚乙烯乙烯醇的基本性質與應用 ................................ 34
2.5.2 聚乙烯乙烯醇的成膜機制 ............................................ 35
2.6 磁性奈米粒子 ...................................................................... 36
2.6.1 磁性奈米粒子的製備方法 ............................................ 36
2.6.2 毒性與生物相容性 ........................................................ 38
2.6.3 磁性奈米粒子的應用 .................................................... 38
第三章 實驗儀器與步驟 ...................................................................... 40
3.1 實驗藥品與儀器 .................................................................. 40
3.1.1 實驗藥品 ........................................................................ 40
3.1.2 實驗材料 ........................................................................ 43
3.1.3 實驗儀器 ........................................................................ 44
3.1.4 儀器原理 ........................................................................ 46
3.2 分子拓印磁性奈米粒子 ...................................................... 51
3.2.1 製備磁性奈米粒子 ........................................................ 51
3.2.2 分子拓印高分子複合磁性奈米粒子 ............................ 51
3.2.3 花青素 540 複合磁性奈米粒子 .................................... 51
3.2.4 複合磁性奈米粒子之吸附能力分析 ............................ 52
3.2.5 複合磁性奈米粒子之分析 ............................................ 52
3.3 細胞培養 .............................................................................. 53
3.3.1 磷酸緩衝溶液配製 ........................................................ 53
3.3.2 細胞培養基配製 ............................................................ 53
3.3.3 細胞之繼代培養 ............................................................ 54
3.4 細胞實驗 .............................................................................. 56
3.4.1 細胞毒性實驗 ................................................................ 56
3.4.2 細胞核染色 .................................................................... 56
3.4.3 免疫染色 ........................................................................ 56
3.4.4 即時定量聚合酶反應器步驟 ........................................ 57
3.4.5 免疫療法 ........................................................................ 57
3.4.6 光動力治療 .................................................................... 58
3.4.7 CC kit 8 細胞毒性實驗 ................................................... 58
第四章 結果與討論 .............................................................................. 60
4.1 胜肽 A 拓印聚乙烯乙烯醇複合微粒的粒徑變化 ............. 60
4.2 胜肽 A 拓印聚乙烯乙烯醇複合微粒性質分析 ................. 63
4.2.1 胜肽拓印濃度對吸附量的影響 .................................... 63
4.2.2 複合微粒吸附時間之再吸附量 .................................... 65
4.2.3 複合微粒等溫吸附 ........................................................ 66
4.2.4 以 SQUID 量測複合微粒的磁化曲線 ........................... 68
4.2.5 以 BET 量測 AIPs 的比表面積 ..................................... 69
4.3 複合微粒對細胞生存率的影響及其應用 .......................... 70
4.3.1 改變 NK-92 細胞濃度對 HepG2 細胞存活率影響 ..... 70
4.3.2 利用 SEM 來觀察 HepG2/NK-92 ................................. 73
4.3.3 免疫/DAPI 染色 ............................................................. 75
4.3.4 改變 AIPs 的濃度觀察阻斷 PD-1 與 PD-L1 之效果 ... 79
4.3.5 利用 CCKit 8 分析 AIPs 的免疫治療 ........................... 81
4.4 免疫治療誘導 HepG2 凋亡的信號傳導路徑 ..................... 83
4.5 胜肽 E 拓印聚乙烯乙烯醇複合微粒的粒徑變化 .............. 85
4.6 胜肽 E 拓印聚乙烯乙烯醇複合微粒性質分析 .................. 89
4.6.1 胜肽拓印濃度對吸附量的影響 .................................... 89
4.6.2 複合微粒吸附時間之再吸附量 .................................... 90
4.6.3 複合微粒等溫吸附 ........................................................ 91
4.6.4 以 SQUID 量測複合微粒的磁化曲線 .......................... 93
4.6.5 以 BET 量測 EIPs 的比表面積 ..................................... 94
4.6.6 以 FTIR 測量複合微粒的表面官能基 ......................... 95
4.7 複合微粒對細胞生存率的影響及其應用 .......................... 96
4.7.1 複合微粒對 HepG2 細胞毒性的影響 ........................... 96
4.7.2 利用光驅動光動藥物對 HepG2 生存率的影響 .......... 99
4.7.3 利用 CC Kit8 分析 EIPs 對 HepG2 的光動力治療 ... 102
4.7.4 PDT 誘導光敏藥物的信號傳導途徑 ........................... 105
4.8 光動力療法與免疫療法結合對 HepG2 細胞生存率的影響

............................................................................................................. 111
第五章 結論......................................................................................... 113
參考文獻 ................................................................................................. 115
附錄 ......................................................................................................... 127

[1] 衛生福利部"<105 年死因統計結果分析>."
[2] H. B. El-Serag, "Epidemiology of viral hepatitis and hepatocellular carcinoma," Gastroenterology, vol. 142, pp. 12641273 e1, May 2012.
[3] S. J. Hutchinson, S. M. Bird, and D. J. Goldberg, "Influence of alcohol on the progression of hepatitis C virus infection: a metaanalysis," Clinical Gastroenterology and Hepatology, vol. 3, pp. 1150-1159, 2005.
[4] S. Mittal and H. B. El-Serag, "Epidemiology of hepatocellular carcinoma: consider the population," J Clin Gastroenterol, vol. 47 Suppl, pp. S2-6, Jul 2013.
[5] M. Colombo, R. De Franchis, E. Del Ninno, A. Sangiovanni, C. De Fazio, M. Tommasini, et al., "Hepatocellular carcinoma in Italian patients with cirrhosis," New England Journal of Medicine, vol. 325, pp. 675-680, 1991.
[6] R. Dhanasekaran, S. Bandoh, and L. R. Roberts, "Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances," F1000Res, vol. 5, 2016.
[7] M. S. Chen, J. Q. Li, Y. Zheng, R. P. Guo, H. H. Liang, Y. Q. Zhang, et al., "A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma," Ann Surg, vol. 243, pp. 321-8, Mar 2006.
[8] S. Shiina, K. Tagawa, T. Unuma, R. Takanashi, K. Yoshiura, Y. Komatsu, et al., "Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study," Cancer, vol. 68, pp. 1524-1530, 1991.
[9] S. Shiina, H. Yasuda, H. Muto, K. Tagawa, T. Unuma, K. Ibukuro, et al., "Percutaneous ethanol injection in the treatment of liver neoplasms," American Journal of Roentgenology, vol. 149, pp. 949952, 1987.
[10] R. Yamada, M. Sato, M. Kawabata, H. Nakatsuka, K. Nakamura, and S. Takashima, "Hepatic artery embolization in 120 patients with unresectable hepatoma," Radiology, vol. 148, pp. 397-401, 1983.
[11] N. Nakao, K. Miura, H. Takahashi, M. Ohnishi, T. Miura, E. Okamoto, et al., "Hepatocellular carcinoma: combined hepatic, arterial, and portal venous embolization," Radiology, vol. 161, pp. 303-307, 1986.
[12] M. Feng and E. Ben-Josef, "Radiation therapy for hepatocellular carcinoma," Semin Radiat Oncol, vol. 21, pp. 271-7, Oct 2011.
[13] M. A. Hawkins and L. A. Dawson, "Radiation therapy for hepatocellular carcinoma: from palliation to cure," Cancer, vol. 106, pp. 1653-63, Apr 15 2006.
[14] J. DePry, J. Brescoll, L. Szczotka-Flynn, P. Rambhatla, H. W. Lim, and K. Cooper, "Phototherapy-related ophthalmologic disorders," Clin Dermatol, vol. 33, pp. 247-55, Mar-Apr 2015.
[15] R. Malik, A. Manocha, and D. Suresh, "Photodynamic therapy-A strategic review," Indian Journal of Dental Research, vol. 21, p. 285, 2010.
[16] K. JURCZYSZYN, P. ZIÓŁKOWSKI, H. GERBER, and B. J. OSIECKA, "Potentiality of Photodynamic Therapy in Dentistry," Dent. Med. Probl, vol. 44, pp. 255-258, 2007.
[17] T. J. Dougherty, C. J. Gomer, B. W. Henderson, G. Jori, D. Kessel, M. Korbelik, et al., "Photodynamic therapy," JNCI: Journal of the National Cancer Institute, vol. 90, pp. 889-905, 1998.
[18] P. Agostinis, K. Berg, K. A. Cengel, T. H. Foster, A. W. Girotti, S. O. Gollnick, et al., "Photodynamic therapy of cancer: an update," CA Cancer J Clin, vol. 61, pp. 250-81, Jul-Aug 2011.
[19] G. R. Buettner, "Spin Trapping: ESR parameters of spin adducts 1474 1528V," Free Radical Biology and Medicine, vol. 3, pp. 259-303, 1987.
[20] A. P. Castano, T. N. Demidova, and M. R. Hamblin, "Mechanisms in photodynamic therapy: part one— photosensitizers, photochemistry and cellular localization," Photodiagnosis and Photodynamic Therapy, vol. 1, pp. 279-293, 2004.
[21] T. H. Foster, R. S. Murant, R. G. Bryant, R. S. Knox, S. L. Gibson, and R. Hilf, "Oxygen consumption and diffusion effects in photodynamic therapy," Radiation research, vol. 126, pp. 296-303, 1991.
[22] E. Buytaert, M. Dewaele, and P. Agostinis, "Molecular effectors of multiple cell death pathways initiated by photodynamic therapy," Biochim Biophys Acta, vol. 1776, pp. 86-107, Sep 2007.
[23] N. Festjens, T. Vanden Berghe, and P. Vandenabeele, "Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response," Biochim Biophys Acta, vol. 1757, pp. 1371-87, Sep-Oct 2006.
[24] Y. Tian, W. Leung, K. Yue, and N. Mak, "Cell death induced by MPPa-PDT in prostate carcinoma in vitro and in vivo," Biochem Biophys Res Commun, vol. 348, pp. 413-20, Sep 22 2006.
[25] D. Glick, S. Barth, and K. F. Macleod, "Autophagy: cellular and molecular mechanisms," J Pathol, vol. 221, pp. 3-12, May 2010.
[26] A. Chiaviello, I. Postiglione, and G. Palumbo, "Targets and mechanisms of photodynamic therapy in lung cancer cells: a brief overview," Cancers (Basel), vol. 3, pp. 1014-41, Mar 3 2011.
[27] A. Karioti and A. R. Bilia, "Hypericins as potential leads for new therapeutics," International journal of molecular sciences, vol. 11, pp. 562-594, 2010.
[28] R. Allison, K. Moghissi, G. Downie, and K. Dixon, "Photodynamic therapy (PDT) for lung cancer," Photodiagnosis Photodyn Ther, vol. 8, pp. 231-9, Sep 2011.
[29] A. E. O'Connor, W. M. Gallagher, and A. T. Byrne, "Porphyrin and nonporphyrin photosensitizers in oncology: preclinical and clinical advances in photodynamic therapy," Photochem Photobiol, vol. 85, pp. 1053-74, Sep-Oct 2009.
[30] A. B. Ormond and H. S. Freeman, "Dye Sensitizers for Photodynamic Therapy," Materials (Basel), vol. 6, pp. 817-840, Mar 6 2013.
[31] C. Morton, S. Brown, S. Collins, S. Ibbotson, H. Jenkinson, H. Kurwa, et al., "Guidelines for topical photodynamic therapy: report of a workshop of the British Photodermatology Group," British Journal of Dermatology, vol. 146, pp. 552-567, 2002.
[32] A. Rück and R. Steiner, "Basic reaction mechanisms of hydrophilic and lipophilic photosensitisers in photodynamic tumour
treatment," Minimally Invasive Therapy & Allied Technologies, vol. 7, pp. 503-509, 1998.
[33] C. K. Lim, J. Heo, S. Shin, K. Jeong, Y. H. Seo, W. D. Jang, et al., "Nanophotosensitizers toward advanced photodynamic therapy of Cancer," Cancer Lett, vol. 334, pp. 176-87, Jul 1 2013.
[34] J. Zhao, J. Fei, L. Gao, W. Cui, Y. Yang, A. Wang, et al., "Bioluminescent microcapsules: applications in activating a photosensitizer," Chemistry, vol. 19, pp. 4548-55, Apr 2 2013.
[35] Z. Diwu and J. W. Lown, "Phototherapeutic potential of alternative photosensitizers to porphyrins," Pharmacology & therapeutics, vol. 63, pp. 1-35, 1994.
[36] E. Delaey, F. van Laar, D. De Vos, A. Kamuhabwa, P. Jacobs, and P. de Witte, "A comparative study of the photosensitizing characteristics of some cyanine dyes," Journal of Photochemistry and Photobiology B: Biology, vol. 55, pp. 27-36, 2000.
[37] K. Kassab, "Photophysical and photosensitizing properties of selected cyanines," Journal of Photochemistry and Photobiology B: Biology, vol. 68, pp. 15-22, 2002.
[38] J. Chen, N. Cheung, M. Fung, J. Wen, W. Leung, and N. Mak, "Subcellular Localization of Merocyanine 540 (MC540) and Induction of Apoptosis in Murine Myeloid Leukemia Cells¶," Photochemistry and photobiology, vol. 72, pp. 114-120, 2000.
[39] B. Čunderlı́ková and L. Šikurová, "Solvent effects on photophysical properties of merocyanine 540," Chemical Physics, vol. 263, pp. 415-422, 2001. [40] F. Sieber, "MEROCYANINE 540," Photochemistry and photobiology, vol. 46, pp. 1035-1042, 1987.
[41] Y. C. Chen and J. K. Lin, "Photodynamic anticancer agent merocyanine540 inhibits cell growth by apoptosis," Anticancer research, vol. 16, pp. 2781-2788, 1996.
[42] P. Nowak-Sliwinska, A. Karocki, M. Elas, A. Pawlak, G. Stochel, and K. Urbanska, "Verteporfin, photofrin II, and merocyanine 540 as PDT photosensitizers against melanoma cells," Biochem Biophys Res Commun, vol. 349, pp. 549-55, Oct 20 2006.
[43] C. Yow, N. Mak, S. Szeto, J. Chen, Y. Lee, N. Cheung, et al., "Photocytotoxic and DNA damaging effect of temoporfin (mTHPC) and merocyanine 540 (MC540) on nasopharyngeal carcinoma cell," Toxicology letters, vol. 115, pp. 53-61, 2000.
[44] F. Burnet, "Immunological surveillance in neoplasia," Immunological Reviews, vol. 7, pp. 3-25, 1971.
[45] M. W. L. Teng, M. H. Kershaw, and M. J. Smyth, "Cancer Immunoediting," pp. 85-99, 2013.
[46] E. F. Redente, C. V. Jakubzick, T. R. Martin, and D. W. H. Riches, "Innate Immunity," pp. 184-205.e7, 2016.
[47] D. Mason, "Lymphocytes A2 - Delves, Peter J," in Encyclopedia of Immunology (Second Edition), ed Oxford: Elsevier, 1998, pp. 1625-1627.
[48] G. P. Dunn, A. T. Bruce, H. Ikeda, L. J. Old, and R. D. Schreiber, "Cancer immunoediting: from immunosurveillance to tumor escape," Nature immunology, vol. 3, p. 991, 2002.
[49] G. P. Dunn, L. J. Old, and R. D. Schreiber, "The immunobiology of cancer immunosurveillance and immunoediting," Immunity, vol. 21, pp. 137-148, 2004. [50] G. P. Dunn, L. J. Old, and R. D. Schreiber, "The immunobiology of cancer immunosurveillance and immunoediting," Immunity, vol. 21, pp. 137-48, Aug 2004.
[51] T. A. Waldmann, "Immunotherapy: past, present and future," Nature medicine, vol. 9, p. 269, 2003.
[52] D. N. Khalil, E. L. Smith, R. J. Brentjens, and J. D. Wolchok, "The future of cancer treatment: immunomodulation, CARs and combination immunotherapy," Nat Rev Clin Oncol, vol. 13, pp. 27390, May 2016.
[53] J. Bruix, M. Sherman, J. M. Llovet, M. Beaugrand, R. Lencioni, A. K. Burroughs, et al., "Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference," Journal of hepatology, vol. 35, pp. 421-430, 2001.
[54] J. M. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J.-F. Blanc, et al., "Sorafenib in advanced hepatocellular carcinoma," New England journal of medicine, vol. 359, pp. 378-390, 2008.
[55] J. Prieto, I. Melero, and B. Sangro, "Immunological landscape and immunotherapy of hepatocellular carcinoma," Nat Rev Gastroenterol Hepatol, vol. 12, pp. 681-700, Dec 2015.
[56] J.-F. Brunet, F. Denizot, M.-F. Luciani, M. Roux-Dosseto, M. Suzan, M.-G. Mattei, et al., "A new member of the immunoglobulin superfamily—CTLA-4," Nature, vol. 328, p. 267, 1987.
[57] M. F. Krummel, "CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation," Journal of Experimental Medicine, vol. 182, pp. 459-465, 1995.
[58] F. S. Hodi, S. J. O'day, D. F. McDermott, R. W. Weber, J. A. Sosman, J. B. Haanen, et al., "Improved survival with ipilimumab in patients with metastatic melanoma," New England Journal of Medicine, vol. 363, pp. 711-723, 2010.
[59] H. Dong, G. Zhu, K. Tamada, and L. Chen, "B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion," Nature medicine, vol. 5, p. 1365, 1999.
[60] T. Okazaki, S. Chikuma, Y. Iwai, S. Fagarasan, and T. Honjo, "A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application," Nature immunology, vol. 14, p. 1212, 2013.
[61] C. Robert, G. V. Long, B. Brady, C. Dutriaux, M. Maio, L. Mortier, et al., "Nivolumab in previously untreated melanoma without BRAF mutation," New England journal of medicine, vol. 372, pp. 320-330, 2015.
[62] R. Das, R. Verma, M. Sznol, C. S. Boddupalli, S. N. Gettinger, H. Kluger, et al., "Combination therapy with anti-CTLA-4 and antiPD-1 leads to distinct immunologic changes in vivo," J Immunol, vol. 194, pp. 950-9, Feb 1 2015.
[63] J. Larkin, V. Chiarion-Sileni, R. Gonzalez, J. J. Grob, C. L. Cowey, C. D. Lao, et al., "Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma," N Engl J Med, vol. 373, pp. 23-34, Jul 2 2015.
[64] Z. Zeng, F. Shi, L. Zhou, M. N. Zhang, Y. Chen, X. J. Chang, et al., "Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma," PLoS One, vol. 6, p. e23621, 2011.
[65] R. Kiessling, E. Klein, and H. Wigzell, "„Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype," European journal of immunology, vol. 5, pp. 112-117, 1975.
[66] T. L. Geiger and J. C. Sun, "Development and maturation of natural killer cells," Curr Opin Immunol, vol. 39, pp. 82-9, Apr 2016.
[67] A. G. Freud, J. Yu, and M. A. Caligiuri, "Human natural killer cell development in secondary lymphoid tissues," Semin Immunol, vol. 26, pp. 132-7, Apr 2014.
[68] Z. Shuai, M. W. Leung, X. He, W. Zhang, G. Yang, P. S. Leung, et al., "Adaptive immunity in the liver," Cell Mol Immunol, vol. 13, pp. 354-68, May 2016.
[69] H. Peng, E. Wisse, and Z. Tian, "Liver natural killer cells: subsets and roles in liver immunity," Cell Mol Immunol, vol. 13, pp. 328-36, May 2016. [70] I. B. Alvarez, V. Pasquinelli, J. O. Jurado, E. Abbate, R. M. Musella, S. S. de la Barrera, et al., "Role played by the programmed death-1-programmed death ligand pathway during innate immunity against Mycobacterium tuberculosis," J Infect Dis, vol. 202, pp. 524-32, Aug 15 2010.
[71] S. Pesce, M. Greppi, G. Tabellini, F. Rampinelli, S. Parolini, D. Olive, et al., "Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization," J Allergy Clin Immunol, vol. 139, pp. 335-346 e3, Jan 2017. [72] Y. Liu, Y. Cheng, Y. Xu, Z. Wang, X. Du, C. Li, et al., "Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers," Oncogene, vol. 36, pp. 6143-6153, Nov 2 2017.
[73] E. Vivier, E. Tomasello, M. Baratin, T. Walzer, and S. Ugolini, "Functions of natural killer cells," Nat Immunol, vol. 9, pp. 503-10, May 2008.
[74] T. Floros and A. A. Tarhini, "Anticancer cytokines: biology and clinical effects of interferon-α2, interleukin (IL)-2, IL-15, IL-21, and IL-12," in Seminars in oncology, 2015, pp. 539-548.
[75] D. Peer, J. M. Karp, S. Hong, O. C. Farokhzad, R. Margalit, and R. Langer, "Nanocarriers as an emerging platform for cancer therapy," Nature nanotechnology, vol. 2, p. 751, 2007.
[76] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, and K. Hori, "Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review," Journal of controlled release, vol. 65, pp. 271-284, 2000.
[77] F. X. Gu, R. Karnik, A. Z. Wang, F. Alexis, E. Levy-Nissenbaum, S. Hong, et al., "Targeted nanoparticles for cancer therapy," Nano Today, vol. 2, pp. 14-21, 2007.
[78] J. Fang, H. Nakamura, and H. Maeda, "The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect," Adv Drug Deliv Rev, vol. 63, pp. 136-51, Mar 18 2011.
[79] B. D. Chithrani, A. A. Ghazani, and W. C. Chan, "Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells," Nano letters, vol. 6, pp. 662-668, 2006.
[80] F. Gentile, C. Chiappini, D. Fine, R. C. Bhavane, M. S. Peluccio, M. M. Cheng, et al., "The effect of shape on the margination dynamics of non-neutrally buoyant particles in two-dimensional shear flows," J Biomech, vol. 41, pp. 2312-8, Jul 19 2008.
[81] F. Alexis, E. Pridgen, L. K. Molnar, and O. C. Farokhzad, "Factors affecting the clearance and biodistribution of polymeric nanoparticles," Molecular pharmaceutics, vol. 5, pp. 505-515, 2008.
[82] H. Lee, A. K. Lytton-Jean, Y. Chen, K. T. Love, A. I. Park, E. D. Karagiannis, et al., "Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery," Nat Nanotechnol, vol. 7, pp. 389-93, Jun 3 2012.
[83] X. Zang, X. Zhao, H. Hu, M. Qiao, Y. Deng, and D. Chen, "Nanoparticles for tumor immunotherapy," Eur J Pharm Biopharm, vol. 115, pp. 243-256, Jun 2017.
[84] S. D. Jo, G.-H. Nam, G. Kwak, Y. Yang, and I. C. Kwon, "Harnessing designed nanoparticles: Current strategies and future perspectives in cancer immunotherapy," Nano Today, vol. 17, pp. 23-37, 2017.
[85] L. Pauling, "A theory of the structure and process of formation of antibodies," Journal of the American Chemical Society, vol. 62, pp. 2643-2657, 1940.
[86] K. Haupt and K. Mosbach, "Molecularly imprinted polymers and their use in biomimetic sensors," Chemical reviews, vol. 100, pp. 2495-2504, 2000.
[87] R. Arshady and K. Mosbach, "Synthesis of substrate-selective polymers by host-guest polymerization," Die Makromolekulare Chemie: Macromolecular Chemistry and Physics, vol. 182, pp. 687692, 1981.
[88] X. Liu, Y. Guan, H. Liu, Z. Ma, Y. Yang, and X. Wu, "Preparation and characterization of magnetic polymer nanospheres with high protein binding capacity," Journal of Magnetism and Magnetic Materials, vol. 293, pp. 111-118, 2005.
[89] M. Shao, F. Ning, J. Zhao, M. Wei, D. G. Evans, and X. Duan, "Preparation of Fe3O4@SiO2@layered double hydroxide core-shell microspheres for magnetic separation of proteins," J Am Chem Soc, vol. 134, pp. 1071-7, Jan 18 2012. [90] X. Yu, H. Liu, J. Diao, Y. Sun, and Y. Wang, "Magnetic molecularly imprinted polymer nanoparticles for separating aromatic amines from azo dyes – Synthesis, characterization and application," Separation and Purification Technology, vol. 204, pp. 213-219, 2018.
[91] E. Turiel and A. Martin-Esteban, "Molecularly imprinted polymers for sample preparation: a review," Anal Chim Acta, vol. 668, pp. 87-99, Jun 4 2010.
[92] K. Haupt, "Peer reviewed: molecularly imprinted polymers: the next generation," ed: ACS Publications, 2003.
[93] S. Beyazit, B. Tse Sum Bui, K. Haupt, and C. Gonzato, "Molecularly imprinted polymer nanomaterials and nanocomposites by controlled/living radical polymerization," Progress in Polymer Science, vol. 62, pp. 1-21, 2016. [94] C. Wang, A. Javadi, M. Ghaffari, and S. Gong, "A pH-sensitive molecularly imprinted nanospheres/hydrogel composite as a coating for implantable biosensors," Biomaterials, vol. 31, pp. 494451, Jun 2010.
[95] J. Li, R. Dong, X. Wang, H. Xiong, S. Xu, D. Shen, et al., "Onepot synthesis of magnetic molecularly imprinted microspheres by RAFT precipitation polymerization for the fast and selective removal of 17β-estradiol," RSC Advances, vol. 5, pp. 10611-10618, 2015.
[96] M. Glad, O. Norrlöw, B. Sellergren, N. Siegbahn, and K. Mosbach, "Use of silane monomers for molecular imprinting and enzyme entrapment in polysiloxane-coated porous silica," Journal of Chromatography A, vol. 347, pp. 11-23, 1985.
[97] H.-Y. Lin, C.-Y. Hsu, J. L. Thomas, S.-E. Wang, H.-C. Chen, and T.C. Chou, "The microcontact imprinting of proteins: The effect of cross-linking monomers for lysozyme, ribonuclease A and myoglobin," Biosensors and Bioelectronics, vol. 22, pp. 534-543, 2006.
[98] M. Bosserdt, N. Gajovic-Eichelman, and F. W. Scheller, "Modulation of direct electron transfer of cytochrome c by use of a molecularly imprinted thin film," Anal Bioanal Chem, vol. 405, pp. 6437-44, Aug 2013.
[99] A. Bossi, F. Bonini, A. P. Turner, and S. A. Piletsky, "Molecularly imprinted polymers for the recognition of proteins: the state of the art," Biosens Bioelectron, vol. 22, pp. 1131-7, Jan 15 2007.
[100] A. Rachkov and N. Minoura, "Towards molecularly imprinted polymers selective to peptides and proteins. The epitope approach," Biochimica et Biophysica Acta (BBA)-Protein Structure and Molecular Enzymology, vol. 1544, pp. 255-266, 2001.
[101] M.-H. Lee, J. L. Thomas, C.-L. Liao, S. Jurcevic, T. CrnogoracJurcevic, and H.-Y. Lin, "Epitope recognition of peptide-imprinted polymers for Regenerating protein 1 (REG1)," Separation and Purification Technology, vol. 192, pp. 213-219, 2018.
[102] R. Tchinda, A. Tutsch, B. Schmid, R. D. Süssmuth, and Z. Altintas, "Recognition of protein biomarkers using epitopemediated molecularly imprinted films: Histidine or cysteine modified epitopes?," Biosensors and Bioelectronics, 2018.
[103] J. Wen and G. L. Wilkes, "Surface modification of ethylenevinyl alcohol (EVOH) copolymer films by the attachment of triethoxysilane functionality," Polymer Bulletin, vol. 37, pp. 51-57, 1996.
[104] M.-H. Lee, T.-C. Tsai, J. L. Thomas, and H.-Y. Lin, "Recognition of creatinine by poly(ethylene-co-vinylalcohol) molecular imprinting membrane," Desalination, vol. 234, pp. 126-133, 2008.
[105] C. Y. Huang, T. C. Tsai, J. L. Thomas, M. H. Lee, B. D. Liu, and H. Y. Lin, "Urinalysis with molecularly imprinted poly(ethylene-co-vinyl alcohol) potentiostat sensors," Biosens Bioelectron, vol. 24, pp. 2611-7, Apr 15 2009. [106] A. Sadeghi, H. Nazem, M. Rezakazemi, and S. Shirazian, "Predictive construction of phase diagram of ternary solutions containing polymer/solvent/nonsolvent using modified FloryHuggins model," Journal of Molecular Liquids, vol. 263, pp. 282-287, 2018.
[107] T.-H. Young and L.-W. Chen, "Pore formation mechanism of membranes from phase inversion process," Desalination, vol. 103, pp. 233-247, 1995.
[108] L. H. Reddy, J. L. Arias, J. Nicolas, and P. Couvreur, "Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications," Chemical reviews, vol. 112, pp. 5818-5878, 2012.
[109] C. S. Lee, H. Lee, and R. M. Westervelt, "Microelectromagnets for the control of magnetic nanoparticles," Applied Physics Letters, vol. 79, pp. 3308-3310, 2001.
[110] S. Mathur, S. Barth, U. Werner, F. Hernandez-Ramirez, and A. Romano-Rodriguez, "Chemical Vapor Growth of One-dimensional Magnetite Nanostructures," Advanced Materials, vol. 20, pp. 15501554, 2008.
[111] R. Massart, "Preparation of aqueous magnetic liquids in alkaline and acidic media," IEEE transactions on magnetics, vol. 17, pp. 1247-1248, 1981. [112] H. Itoh and T. Sugimoto, "Systematic control of size, shape, structure, and magnetic properties of uniform magnetite and maghemite particles," Journal of Colloid and Interface Science, vol. 265, pp. 283-295, 2003.
[113] T. Gonzalez-Carreno, M. Morales, M. Gracia, and C. Serna, "Preparation of uniform γ-Fe2O3 particles with nanometer size by spray pyrolysis," Materials Letters, vol. 18, pp. 151-155, 1993.
[114] M. Arruebo, R. Fernández-Pacheco, M. R. Ibarra, and J. Santamaría, "Magnetic nanoparticles for drug delivery," Nano Today, vol. 2, pp. 22-32, 2007.
[115] M. K. Yu, Y. Y. Jeong, J. Park, S. Park, J. W. Kim, J. J. Min, et al., "Drug-loaded superparamagnetic iron oxide nanoparticles for combined cancer imaging and therapy in vivo," Angew Chem Int Ed Engl, vol. 47, pp. 5362-5, 2008.
[116] P. Couvreur and C. Vauthier, "Nanotechnology: intelligent design to treat complex disease," Pharm Res, vol. 23, pp. 1417-50, Jul 2006.
[117] S. E. Barry, "Challenges in the development of magnetic particles for therapeutic applications," Int J Hyperthermia, vol. 24, pp. 451-66, Sep 2008. [118] Brookhaven 90Plus Nanopaticle Size Analyzer"<90plus.pdf>."
[119] HITACHI HPLC D2000 system"."
[120] B. D. Josephson, "The Discovery of Tunnelling Supercurrents," Europhysics News, vol. 5, pp. 1-5, 2017.
[121] 超導量子干涉儀"."
[122] 即時螢光定量 PCR 手冊"."
[123] 東海大學 量測儀器介紹"<098THU00442002-009.PDF>."
[124] C. J. Kearney, N. Lalaoui, A. J. Freeman, K. M. Ramsbottom, J. Silke, and J. Oliaro, "PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF," Cell Death Differ, vol. 24, pp. 1705-1716, Oct 2017. [125] M. Cargnello and P. P. Roux, "Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases," Microbiol Mol Biol Rev, vol. 75, pp. 50-83, Mar 2011.