2015年根據世界衛生組織（ WHO ）統計顯示，全球有將近880萬人死於癌症，佔了1/6的死亡人口，是為全球第二大死因。在台灣，癌症也已蟬聯35年居10大死因之首，去年因癌症而死亡的人數即4萬7760人，占總死亡人數的27.7%，平均一天130人死亡。而在各類癌症中，口腔癌(含口咽、下咽)為台灣男性佔第四位發生率與死亡率的癌症（每年約7500人罹癌，3000人死亡），甲狀腺癌則為女性前五種好發癌症之一（每年約3500人罹癌）。頭頸部的癌症其手術治療之風險相對其他癌症為高，因為治療過程容易傷及多種重要器官，因此頭頸癌目前的治療多需要手術合併放射治療、標靶治療與化學治療，醫療過程非常複雜繁瑣而化療與放療之副作用亦多，往往對病人造成更多負擔且效果有限。
硼中子捕獲治療（Boron Neutron Capture Therapy, BNCT）最早在1936年被提出，是一種二元療法，即病人必須先注射含硼藥物，接著藉由增強滲透及滯留作用（Enhanced Permeability and Retention, EPR）或標靶特性使藥物聚集於腫瘤區域，最後再施以熱中子（Thermal Neutron）照射。熱中子會高度專一的被硼原子吸收並放射出高能重粒子，其殺傷範圍大約是一顆癌細胞的半徑，因此這項療法有極佳的針對性，在近數十年，日本、芬蘭、阿根廷、中國均在BNCT有長足發展。然而BNCT目前待突破的一大關鍵即是提高硼原子在腫瘤部位的聚積濃度，現今臨床上的兩種用藥：BPA（para-Borophenylalanine）與BSH（Disodium Mercaptoun-Decahydrododecabotate）均只能藉由持續注射藥物，維持血中藥物濃度再由擴散的方式使藥物進入腫瘤部位，此法對於生理代謝造成很大的負擔，且成本高昂又浪費。長年臨床研究最終也發現BSH對癌細胞之聚積性與一般細胞無太大差異，現已逐漸被淘汰。近年發現，硼酸亦在BNCT上有良好成效，其低成本、低毒性等優點，在未來被認為有發展潛力。
奈米藥物載體之大小約為數十至數百奈米，具有高生物利用度、藥物保護性、藥物緩釋功能以及穿越生物屏障限制等特性，如又於其表面修飾功能性分子，還能降低藥物引發的免疫反應或賦予藥物專一性標靶等特性。因此，本實驗將製備出10nm～2000nm間不同尺寸的聚乙烯醇-硼酸奈米顆粒並分析不同粒徑的藥物在口腔癌細胞的硼中子捕獲治療療效。

According to record by WHO, 2015, there are 8.8 million lives are deprived from cancer. It is the second leading cause of death in the world. In Taiwan, cancer has also been the top 10 death cause for over 35 years. About 47.76 thousand people were killed by cancer last year, accounting for 27.7% in the whole death toll. Among all cancer types, Oral Cancer (including velum and pharynx) takes the 4th places for both occurrence rate and death rate in male (7,500 new cases, 300 die per year), while Thyroid cancer takes the 5th occurrence rate in female (3,500 new cases). Head and Neck cancer poses a rather higher risk in surgery due to unavoidable contact to several vital organs and neuron system. There by, current Head and Neck cancer treatment usually requires combination of radiation therapy, target therapy and chemotherapy, and a well-trained medical team, composing of all necessary divisions is also claimed. Such complicated and trivial treatment often put further pressures on the patients not only physically but mentally. The effects are limited and unpredictable.

Boron Neutron Capture Therapy (BNCT) was first proposed in 1936. It is a binary therapy followed by a series of principals and processes. Firstly, the patients need to be injected by boron enriched drugs, and by the effect of Enhanced Permeability and Retention effect (EPR), the drugs would accumulate in tumor. Next, the patients shall accept epithermal or thermal neutron irradiation. Finally, the neutrons will be captured by boron-10 isotope, generating high energy particles, 4He and 7Li, which can cause DNAs double strain break (DSB), an irreparable and permanent damage against cancer cell. The remarkable feature of this therapy is its high energy particles are limited within a radius of cell, and since the thermal neutron has little effect on pathway cell, the damage range would only limit to tumor lesion. In past 10 years, Japan, Finland, Argentina and China have significant progresses on BNCT field. However, there are still some critical difficulties need to be conquered, one of it is to elevate 10B concentration in tumor. Recently, two FDA approved drugs for BNCT, BPA (para-Borophenylalanine) and BSH (Disodium Mercaptoun-Decahydrododecabotate) can only diffuse in tumor lesion by maintaining a high drug concentration in circulatory system, which is waste and costly. For BSH, due to low distinguished affinity between cancer cell and normal cell, it was seldom used now. Fortunately, there are still other potential boron drugs or boron drug carriers are developing. Boric Acid was founded to be a potent boron agent in recent years for its cost and toxicity are relatively low but still presenting a significant efficacy.

The size of nanodrugs is generally defined from 10 to 1,000nm. It shows several features such as high bio-viability, drug protection, controllable release and bio barrier penetration. Furthermore, some grafted functional molecules can render these nanoparticles specific capabilities to reduce drug adverse reaction (ADR) and elevate targeting specificity. This study will focus on fabrication and BNCT efficacy on oral cancer with Boric Acid-PVA nanoparticles in different sizes from 10nm to 2,000nm.

章節目錄
第一章 緒論 1
1.1研究背景 1
1.1.1硼中子俘獲治療 1
1.1.2奈米藥物 3
1.2研究動機 6
1.2.1癌症療法之發展 6
1.2.2癌症療法之現況與瓶頸 7
1.2.3硼中子捕獲治療的發展優勢 12
第二章 文獻回顧 18
2.1 聚乙烯醇奈米粒子 18
2.2 聚乙烯醇的生物相容性 18
2.3硼中子捕獲治療 19
2.3.1 口腔癌 19
2.3.2 膠質母細胞瘤 22
2.3.3 黑色素瘤 24
2.4 奈米藥物之特性 25
2.4.1 表面電位 25
2.4.2奈米粒子之粒徑 25
2.5 二甲基亞碸之毒性 27
第三章 實驗設計與規劃 29
3.1藥物設計 29
3.1.1藥物開發目標 29
3.1.2藥物設計方針 29
3.1.3藥物製造原理 33
3.1.4實驗藥品 35
3.1.5藥物製造步驟 42
3.1.4實驗用細胞 43
3.2奈米藥物理論分析 44
3.2.1藥物模型 44
3.2.2硼酸理論載藥量分析 47
3.2.3奈米藥物組成元素之中子捕獲比率 48
3.3藥物特性實證規劃 49
3.3.1硼酸-聚乙烯醇奈米藥物之包覆率與洩漏率 49
3.3.2硼酸-聚乙烯醇奈米藥物之生物相對效應 50
3.4細胞毒殺實驗設計 51
3.4.1細胞生長特性試驗設計 51
3.4.2克隆試驗 53
3.4.3藥物天然毒性試驗設計 54
3.4.4純放射環境傷害試驗設計 56
3.4.5硼中子捕獲治療設計 57
3.5細胞攝食試驗 62
3.5.1雷射共軛焦顯微鏡與螢光顯微鏡檢測設計 62
3.5.2感應耦合電漿質譜儀檢測設計 63
第四章 結果與討論 64
4.1硼酸-聚乙烯醇奈米藥物 64
4.1.1藥物顆粒尺寸 64
4.1.2二甲基亞碸比例對藥物的影響 67
4.1.3硼酸比例對藥物的影響 68
4.1.4藥物顆粒於其他溶液中的尺寸變化 70
4.1.5不同分子量的聚乙烯醇對藥物的影響 72
4.1.6不同二甲基亞碸混溶之速度對藥物的影響 76
4.1.7載藥率 81
4.1.8洩漏率 82
4.3細胞毒殺結果 85
4.3.1藥物自身毒性 86
4.3.2藥物以硼中子捕獲治療後的毒性 93
4.4雷射共軛焦與螢光結果 103
第五章 結論 107
參考資料 109

[1] Devita, V. T., & Rosenberg, S. A. (2012). Two Hundred Years of Cancer Research. New England Journal of Medicine, 366(23), 2207-2214.
[2] Fouad, R. R., Aljohani, H. A., & Shoueir, K. R. (2016). Biocompatible poly(vinyl alcohol) nanoparticle-based binary blends for oil spill control. Marine Pollution Bulletin, 112(1-2), 46-52.
[3] Stokes, W.; Berghmans, H. Journal of Polymer Science: Part B: Polymer Physics, 29, 609, 1991.
[4] Inoue, H., Kuwahara, S., & Katayama, K. (2013). The whole process of phase transition and relaxation of poly(N-isopropylacrylamide) aqueous solution. Physical Chemistry Chemical Physics, 15(11), 3814.
[5] Edmondson, S., Nguyen, N. T., Lewis, A. L., & Armes, S. P. (2010). Co-Nonsolvency Effects for Surface-Initiated Poly(2-(methacryloyloxy)ethyl phosphorylcholine) Brushes in Alcohol/Water Mixtures. Langmuir, 26(10), 7216-7226.
[6] Pica, A., & Graziano, G. (2015). On the effect of sodium salts on the coil-to-globule transition of poly(N-isopropylacrylamide). Physical Chemistry Chemical Physics, 17(41), 27750-27757.
[7] Pica, A., & Graziano, G. (2017). Why does TMAO stabilize the globule state of PNIPAM? Polymer,124, 101-106.
[8] Scherzinger, C., Schwarz, A., Bardow, A., Leonhard, K., & Richtering, W. (2014). Cononsolvency of poly-N-isopropyl acrylamide (PNIPAM): Microgels versus linear chains and macrogels. Current Opinion in Colloid & Interface Science, 19(2), 84-94.
[9] Pica, A., & Graziano, G. (2016). An alternative explanation of the cononsolvency of poly(N-isopropylacrylamide) in water–methanol solutions. Physical Chemistry Chemical Physics, 18(36), 25601-25608.
[10] Vaisman, I. I., & Berkowitz, M. L. (1992). Local structural order and molecular associations in water-DMSO mixtures. Molecular dynamics study. Journal of the American Chemical Society, 114(20), 7889-7896.
[11] Wolf, B. A., & Blaum, G. (1975). Measured and calculated solubility of polymers in mixed solvents: Monotony and cosolvency. Journal of Polymer Science: Polymer Physics Edition, 13(6), 1115-1132.
[12] Akl, M. A., Sarhan, A. A., Shoueir, K. R., & Atta, A. M. (2013). Application of Crosslinked Ionic Poly(Vinyl Alcohol) Nanogel as Adsorbents for Water Treatment. Journal of Dispersion Science and Technology, 34(10), 1399-1408.
[13] Shoueir, K. R., Sarhan, A. A., Atta, A. M., & Akl, M. A. (2016). Macrogel and nanogel networks based on crosslinked poly (vinyl alcohol) for adsorption of methylene blue from aqua system. Environmental Nanotechnology, Monitoring & Management, 5, 62-73.
[14] Pearson, R. M., Hsu, H., Bugno, J., & Hong, S. (2014). Understanding nano-bio interactions to improve nanocarriers for drug delivery. MRS Bulletin, 39(03), 227-237.
[15] Mathematical modeling of controlled drug delivery. (2001). Advanced Drug Delivery Reviews, 48(2-3), 137-138.
[16] Park, J. H., & Oh, N. (2014). Endocytosis and exocytosis of nanoparticles in mammalian cells. International Journal of Nanomedicine, 51.
[17] Hirota, K., & Ter, H. (2012). Endocytosis of Particle Formulations by Macrophages and Its Application to Clinical Treatment. Molecular Regulation of Endocytosis.
[18] Mcmillan, S., Rader, C., Jorfi, M., Pickrell, G., & Foster, E. J. (2017). Mechanically switchable polymer fibers for sensing in biological conditions. Journal of Biomedical Optics, 22(2), 027001.
[19] Prosanov, I., Abdulrahman, S., Thomas, S., Bulina, N., & Gerasimov, K. (2018). Complex of polyvinyl alcohol with boric acid: Structure and use. Materials Today Communications, 14, 77-81.
[20] Prasad, S. R., Kumar, T. S., & Jayakrishnan, A. (2017). Ceramic core with polymer corona hybrid nanocarrier for the treatment of osteosarcoma with co-delivery of protein and anti-cancer drug. Nanotechnology, 29(1), 015101.
[21] Cho, E. C., Xie, J., Wurm, P. A., & Xia, Y. (2009). Understanding the Role of Surface Charges in Cellular Adsorption versus Internalization by Selectively Removing Gold Nanoparticles on the Cell Surface with a I2/KI Etchant. Nano Letters, 9(3), 1080-1084.
[22] Advances in the Regulated Pharmaceutical Use of Dimethyl Sulfoxide USP, Ph.Eur. Sep 01, 2016 By Artie S. McKim, Robert Strub. Volume 2016 Supplement, Issue 3, pg s30—s35
[23] Choi, Y., & Park, K. (2018). Targeting Glutamine Metabolism for Cancer Treatment. Biomolecules & Therapeutics, 26(1), 19-28.
[24] Charles, M. W. (2007). ICRP Publication 103: Recommendations of the ICRP. Radiation Protection Dosimetry, 129(4), 500-507.
[25] Franken, N. A., Rodermond, H. M., Stap, J., Haveman, J., & Bree, C. V. (2006). Clonogenic assay of cells in vitro. Nature Protocols, 1(5), 2315-2319.
[26] Yang, X. (2012). Clonogenic Assay. Bio-protocol 2(10): e187.
[27] https://www.biomart.cn/experiment/430/488/497/17471.htm
[28] Labuschagne, C., Van Den Broek, N., Mackay, G., Vousden, K., & Maddocks, O. (2014). Serine, but Not Glycine, Supports One-Carbon Metabolism and Proliferation of Cancer Cells. Cell Reports,7(4), 1248-1258.
[29] Mehrmohamadi, M., Liu, X., Shestov, A., & Locasale, J. (2014). Characterization of the Usage of the Serine Metabolic Network in Human Cancer. Cell Reports, 9(4), 1507-1519.
[30] Maddocks, O. D., Athineos, D., Cheung, E. C., Lee, P., Zhang, T., Niels J. F. Van Den Broek, . . . Vousden, K. H. (2017). Erratum: Corrigendum: Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature, 548(7665), 122-122.
[31] Palmer, E. E., Hayner, J., Sachdev, R., Cardamone, M., Kandula, T., Morris, P., . . . Kirk, E. P. (2015). Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine. Molecular Genetics and Metabolism, 116(3), 178-186.
[32] Krall, A. S., Xu, S., Graeber, T. G., Braas, D., & Christofk, H. R. (2016). Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nature Communications, 7(1).
[33] Flores, A., Sandoval-Gonzalez, S., Takahashi, R., Krall, A., Sathe, L., Wei, L., . . . Lowry, W. E. (2019). Increased lactate dehydrogenase activity is dispensable in squamous carcinoma cells of origin. Nature Communications, 10(1).
[34] Wise, D. R., & Thompson, C. B. (2010). Glutamine addiction: A new therapeutic target in cancer. Trends in Biochemical Sciences, 35(8), 427-433.
[35] Hensley, C. T., Wasti, A. T., & Deberardinis, R. J. (2013). Glutamine and cancer: Cell biology, physiology, and clinical opportunities. Journal of Clinical Investigation, 123(9), 3678-3684.
[36] Souba, W. W., & Pacitti, A. J. (1992). Review: How Amino Acids Get Into Cells: Mechanisms, Models, Menus, and Mediators. Journal of Parenteral and Enteral Nutrition, 16(6), 569-578.
[37] Akita, N., Maruta, F., Seymour, L. W., Kerr, D. J., Parker, A. L., Asai, T., . . . Miyagawa, S. (2006). Identification of oligopeptides binding to peritoneal tumors of gastric cancer. Cancer Science,97(10), 1075-1081.
[38] Asai, T., & Oku, N. (2005). Liposomalized Oligopeptides in Cancer Therapy. Methods in Enzymology Liposomes, 163-176.
[39] Nakase, I., Noguchi, K., Aoki, A., Takatani-Nakase, T., Fujii, I., & Futaki, S. (2017). Arginine-rich cell-penetrating peptide-modified extracellular vesicles for active macropinocytosis induction and efficient intracellular delivery. Scientific Reports, 7(1).
[40] Phang, J. M., Liu, W., Hancock, C. N., & Fischer, J. W. (2015). Proline metabolism and cancer. Current Opinion in Clinical Nutrition and Metabolic Care, 18(1), 71-77.
[41] Loayza-Puch, F., Rooijers, K., Buil, L. C., Zijlstra, J., Vrielink, J. F., Lopes, R., . . . Agami, R. (2016). Tumour-specific proline vulnerability uncovered by differential ribosome codon reading. Nature,530(7591), 490-494.
[42] Sullivan, L., Gui, D., Hosios, A., Bush, L., Freinkman, E., & Vander Heiden, M. (2015). Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell, 162(3), 552-563.
[43] Coderre JA, Morris GM. The radiation biology of boron neutron capture therapy.
Radiation research. 1999;151(1):1–18.
[44] Kumada H, Takada K. Treatment planning system and patient positioning for boron neutron capture therapy. Therapeutic Radiology and Oncology, 2018;2:50.
[45] Masunaga, S., Sakurai, Y., Tanaka, H., Tano, K., Suzuki, M., Kondo, N., . . . Ono, K. (2014). The dependency of compound biological effectiveness factors on the type and the concentration of administered neutron capture agents in boron neutron capture therapy. SpringerPlus, 3(1).
[46] Egger, A. E., Rappel, C., Jakupec, M. A., Hartinger, C. G., Heffeter, P., & Keppler, B. K. (2009). Development of an experimental protocol for uptake studies of metal compounds in adherent tumor cells. J. Anal. At. Spectrom., 24(1), 51-61.
[47] Carabe-Fernandez, A., Dale, R. G., & Jones, B. (2007). The incorporation of the concept of minimum RBE (RBEmin) into the linear-quadratic model and the potential for improved radiobiological analysis of high-LET treatments. International Journal of Radiation Biology, 83(1), 27-39.
[48] Beaton-Green, Lindsay & A Burn, Trevor & J Stocki, Trevor & Chauhan, Vinita & Wilkins, Ruth. (2011). Development and characterization of an in vitro alpha radiation exposure system. Physics in medicine and biology. 56. 3645-58.
[49] Zhang, F., Yang, J., Tang, L., Wang, W., Sun, K., Ming, Y., . . . Yan, M. (2017). Effect of X-ray irradiation on hepatocarcinoma cells and erythrocytes in salvaged blood. Scientific Reports, 7(1).
[50] Maeda, Kenichiro & Yasui, Hironobu & Matsuura, Taeko & Yamamori, Tohru & Suzuki, Motofumi & Nagane, Masaki & Nam, Jin-Min & Inanami, Osamu & Shirato, Hiroki. (2016). Evaluation of the relative biological effectiveness of spot-scanning proton irradiation in vitro. Journal of radiation research.
[51] Cojoc, M., Peitzsch, C., Kurth, I., Trautmann, F., Kunz-Schughart, L. A., Telegeev, G. D., . . . Dubrovska, A. (2015). Aldehyde Dehydrogenase Is Regulated by β-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells. Cancer Research, 75(7), 1482-1494.
[52] Wang, J. (2004). Microwave digestion with HNO3/H2O2 mixture at high temperatures for determination of trace elements in coal by ICP-OES and ICP-MS. Analytica Chimica Acta, 514(1), 115-124.
[53] Kuehner, E. C., Alvarez, R., Paulsen, P. J., & Murphy, T. J. (1972). Production and analysis of special high-purity acids purified by subboiling distillation. Analytical Chemistry, 44(12), 2050-2056.
[54] Cheung, A., Bax, H. J., Josephs, D. H., Ilieva, K. M., Pellizzari, G., Opzoomer, J., … Karagiannis, S. N. (2016). Targeting folate receptor alpha for cancer treatment. Oncotarget, 7(32), 52553–52574.
[55] Sosnik, A. (2018). From the “Magic Bullet” to Advanced Nanomaterials for Active Targeting in Diagnostics and Therapeutics. Biomedical Applications of Functionalized Nanomaterials, 1-32.
[56] Yoel Sadovsky, Thomas Jansson, Knobil and Neill's Physiology of Reproduction (Fourth Edition), 2015
[57] Wu M.; Gunning W.; Ratnam M. (1999). "Expression of folate receptor type a in relation to cell type, malignancy, and differentiation in ovary, uterus, and cervix". Cancer Epidemiology, Biomarkers & Prevention, 8: 775–783.
[58] Dam, G. M., Themelis, G., Crane, L. M., Harlaar, N. J., Pleijhuis, R. G., Kelder, W., . . . Ntziachristos, V. (2011). Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: First in-human results. Nature Medicine, 17(10), 1315-1319.
[59] Wibowo, A. S., Singh, M., Reeder, K. M., Carter, J. J., Kovach, A. R., Meng, W., . . . Dann, C. E. (2013). Structures of human folate receptors reveal biological trafficking states and diversity in folate and antifolate recognition. Proceedings of the National Academy of Sciences, 110(38), 15180-15188.
[60] Parker, N., Turk, M. J., Westrick, E., Lewis, J. D., Low, P. S., & Leamon, C. P. (2005). Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Analytical Biochemistry, 338(2), 284-293.
[61] Ducker, G. S., & Rabinowitz, J. D. (2017). One-Carbon Metabolism in Health and Disease. Cell Metabolism, 25(1), 27-42.
[62] Stella, B., Arpicco, S., Peracchia, M. T., Desmaële, D., Hoebeke, J., Renoir, M., . . . Couvreur, P. (2000). Design of Folic Acid‐Conjugated Nanoparticles for Drug Targeting. Journal of Pharmaceutical Sciences, 89(11), 1452-1464.
[63] Shen, Z., Li, Y., Kohama, K., Oneill, B., & Bi, J. (2011). Improved drug targeting of cancer cells by utilizing actively targetable folic acid-conjugated albumin nanospheres. Pharmacological Research, 63(1), 51-58.
[64] Wang, S., & Low, P. S. (1998). Folate-mediated targeting of antineoplastic drugs, imaging agents, and nucleic acids to cancer cells. Journal of Controlled Release, 53(1-3), 39-48.
[65] Davies DL, Wilson GM. Diuretics: mechanism of action and clinical application. Drug. 1975;9(3):178-226.
[66] Allen, B. G., Bhatia, S. K., Anderson, C. M., Eichenberger-Gilmore, J. M., Sibenaller, Z. A., Mapuskar, K. A., . . . Fath, M. A. (2014). Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biology, 2, 963-970.
[67] Kanarek, N., Keys, H. R., Cantor, J. R., Lewis, C. A., Chan, S. H., Kunchok, T., . . . Sabatini, D. M. (2018). Histidine catabolism is a major determinant of methotrexate sensitivity. Nature, 559(7715), 632-636.
[68] Champ, C. E., Baserga, R., Mishra, M. V., Jin, L., Sotgia, F., Lisanti, M. P., . . . Simone, N. L. (2013). Nutrient Restriction and Radiation Therapy for Cancer Treatment: When Less Is More. The Oncologist, 18(1), 97-103.
[69] Yura, Y., & Fujita, Y. (2013). Boron neutron capture therapy as a novel modality of radiotherapy for oral cancer: Principle and antitumor effect. Oral Science International, 10(1), 9-14.
[70] National Aeronautics and Space Administration, Science Mission Directorate. (2010). Ultraviolet Waves.
[71] J. Cadet and T. Douki , Formation of UV-induced DNA damage contributing to skin cancer development, Photochem. Photobiol. Sci., 2018, 17 , 1816 -1841
[72] Lang, Peter F.; Smith, Barry C. (2003). "Ionization Energies of Atoms and Atomic Ions". Journal of Chemical Education. 80 (8): 938.
[73] ISO 21348 Definitions of Solar Irradiance Spectral Categories
[74] https://wwwv.tsgh.ndmctsgh.edu.tw/unit/10026/24286
[75] https://www.tankonyvtar.hu/en/tartalom/tamop412A/20110095_fogaszat_angol/ch01s20.
html
[76] Lomax, M., Folkes, L., & Oneill, P. (2013). Biological Consequences of Radiation-induced DNA Damage: Relevance to Radiotherapy. Clinical Oncology, 25(10), 578-585.
[77] Müssig, Dirk. (2013). Re-scanning in scanned ion beam therapy in the presence of organ motion.
[78] ISO 21348 Definitions of Solar Irradiance Spectral Categories
[79] DeSimone, J.M.; Barth, F.M.; Oh, H.J.; Loo, W.S.; Wilson, M.W.; Hetts, S.W.; Parkinson, D.Y.; Maslyn, J.A.; Robbins, G.R.; Yee, C.R.; et al. 3D Printed Absorber for Capturing Chemotherapy Drugs before They Spread through the Body. ACS Cent. Sci. 2019, 5, 419–427.
[80] Chen XC, Oh HJ, Yu JF, et al. Block Copolymer Membranes for Efficient Capture of a Chemotherapy Drug. ACS Macro Lett. 2016;5(8):936–941.
[81] CANDU Fundamentals Neutrons and Neutron Interactions
[82] Fermi National Accelerator Laboratory Neutron Therapy Facility
[83] Schipler, A., & Iliakis, G. (2013). DNA double-strand-break complexity levels and their possible contributions to the probability for error-prone processing and repair pathway choice. Nucleic Acids Research, 41(16), 7589-7605.