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研究生： 方柏凱
Fang, Bo-Kai
論文名稱： 葉酸或人類血清蛋白與聚乙二醇及鬼臼毒素複合體藥物的設計、合成及生物活性
Design, Synthesis, and Biological Evaluation of Folic Acid- or Human Serum Albumin (HSA)-Based Poly(ethylene Glycol)- Podophyllotoxin Conjugate Drug
指導教授： 李文山
Li, Wen-Shan
林文偉
Lin, Wen-Wei
口試委員： 李文山
Li, Wen-Shan
林文偉
Lin, Wen-Wei
杜玲嫻
Tu, Ling-Hsien
口試日期： 2023/07/21
學位類別： 碩士
Master
系所名稱： 化學系
Department of Chemistry
論文出版年： 2023
畢業學年度： 111
語文別： 英文
論文頁數： 70
中文關鍵詞： 葉酸 、人類血清白蛋白 、聚乙二醇 、鬼臼毒素
英文關鍵詞： Folic acid, Human Serum Albumin, Polyethylene Glycol, Podophyllotoxin
研究方法: 實驗設計法
DOI URL： http://doi.org/10.6345/NTNU202301074
論文種類： 學術論文
相關次數： 點閱：84  下載：0 
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    • 對於許多人類癌症腫瘤，葉酸是良好的標靶。人類血清白蛋白 (HSA) 可以靶向腫瘤，由於其具有親水性，半衰期長，增強的通透性和滯留性等優點。藥物的聚乙二醇化可以延長循環壽命，穩定和改善治療活性。鬼臼毒素及其衍生物是許多具有藥理活性的化合物。這些組合可能具有增強的抗癌細胞活性。在這裡，我們合成了三種化合物：聚乙二醇-鬼臼毒素、葉酸¬ 聚乙二醇-鬼臼毒素和人類血清白蛋白-聚乙二醇-鬼臼毒素，並比較了這些化合物對癌細胞的細胞毒性。

    Folic acid is a great targeting agent for several human cancer types. Human Serum Albumin (HSA) is a hydrophilic protein with long half-life time, which can naturally accumulate in tumor cells due to its permeability and retention effects. PEGylation of a drug can enhance circulation lifetime, stability and improve its therapeutic activity. Considering that podophyllotoxin and its derivatives are pharmacologically active compounds, we then propose that the conjugation of folic acid, HSA and PEG may increase the bioactivity against cancer cells. In this study, we prepared three compounds, which are PEG-Podophyllotoxin, Folate-PEG-Podophyllotoxin, and HSA-PEG-Podophyllotoxin, and assess their cytotoxicity towards triple negative breast cancer.

    中文摘要 I Abstract II Content III Scheme Content V Table Content VI List of Abbreviation VIII I. Introduction 1 1.1 Background 1 1.2 Antibody-drug conjugate (ADC) 2 1.3 Folic acid 7 1.4 Human serum albumin (HSA) 8 1.5 Polyethylene glycol (PEG) 12 1.6 Podophyllotoxin 13 II. Result and discussions 14 2.1 Synthetic strategy 14 2.1.1 Synthesis of PEG-Podophyllotoxin conjugate 14 2.1.2 Synthesis of Folate-PEG-Podophyllotoxin conjugate 15 2.1.3 Synthesis of HSA-PEG-Podophyllotoxin conjugate 16 2.1.4 Synthesis of substituent groups 18 2.2 Biological experiments section: in vitro studies 19 2.2.1 The cytotoxicity of BK002, BK004, BK005, and BK006 19 2.3 Experimental failure experiences 22 2.3.1 The failure in the synthesis of BK003 22 2.3.2 The failure in the synthesis of BK005 23 2.3.3 The failure in the synthesis of di-PPT-PEG 24 III. Conclusions 25 IV. Experimental section 26 4.1 General procedures 26 4.2 Synthetic method 27 4.2.1 Preparation of poly(ethylene glycol) derivative 27 4.2.2 Preparation of substituent groups 30 4.2.3 Preparation of BK002 32 4.2.4 Preparation of BK003 33 4.2.5 Preparation of BK004 34 4.2.6 Preparation of BK005 35 4.2.7 Preparation of BK00637 36 4.3 Biological experimental method 36 4.3.1 Cell Line and Cell Culture 36 4.3.2 MTT Cytotoxicity Analysis 37 V. Reference 37 VI. Appendix – Spectra 41

    衛生福利部統計處, (2022), 111年死因統計結果分析, Retrieved June, 14, 2023, from https://dep.mohw.gov.tw/DOS/lp-5069-113-xCat-y111.html.
    Jaracz, S.; Chen, J.; Kuznetsova, L. V.; Ojima, I., Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem 2005, 13 (17), 5043-5054.
    Hafeez, U.; Parakh, S.; Gan, H. K.; Scott, A. M., Antibody-Drug Conjugates for Cancer Therapy. Molecules 2020, 25 (20) 4764.
    Jin, Y.; Schladetsch, M. A.; Huang, X.; Balunas, M. J.; Wiemer, A. J., Stepping forward in antibody-drug conjugate development. Pharmacol Ther 2022, 229, 107917.
    Chia, C. S. B., A Patent Review on FDA-Approved Antibody-Drug Conjugates, Their Linkers and Drug Payloads. ChemMedChem 2022, 17 (11), e202200032.
    Su, Z.; Xiao, D.; Xie, F.; Liu, L.; Wang, Y.; Fan, S.; Zhou, X.; Li, S., Antibody-drug conjugates: Recent advances in linker chemistry. Acta Pharm Sin B 2021, 11 (12), 3889-3907.
    McCombs, J. R.; Owen, S. C., Antibody drug conjugates: design and selection of linker, payload and conjugation chemistry. AAPS J 2015, 17 (2), 339-351.
    Senter, P. D.; Sievers, E. L., The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol 2012, 30 (7), 631-637.
    Tsuchikama, K.; An, Z., Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell 2018, 9 (1), 33-46.
    Philip S. Low, W. A. H., and Derek D. Doorneweerd, Discovery and Development of Folic-Acid-Based Receptor Targeting for Imaging and Therapy of Cancer and Inflammatory Diseases. Accounts of Chemical Research 2008, 41 (1), 120-129.
    Yingjuan Lu, P. S. L., Folate-mediated delivery of macromolecular anticancer therapeutic agents. Advanced Drug Delivery Reviews 2002, 54 (5), 675-693.
    Schneider, R.; Schmitt, F.; Frochot, C.; Fort, Y.; Lourette, N.; Guillemin, F.; Muller, J. F.; Barberi-Heyob, M., Design, synthesis, and biological evaluation of folic acid targeted tetraphenylporphyrin as novel photosensitizers for selective photodynamic therapy. Bioorg Med Chem 2005, 13 (8), 2799-2808.
    Alexander, C. M.; Hamner, K. L.; Maye, M. M.; Dabrowiak, J. C., Multifunctional DNA-gold nanoparticles for targeted doxorubicin delivery. Bioconjug Chem 2014, 25 (7), 1261-1271.
    Leamon, C. P.; Reddy, J. A., Folate-targeted chemotherapy. Adv Drug Deliv Rev 2004, 56 (8), 1127-1141.
    Gao, J.; Jiang, S.; Zhang, X.; Fu, Y.; Liu, Z., Preparation, characterization and in vitro activity of a docetaxel-albumin conjugate. Bioorg Chem 2019, 83, 154-160.
    Tao, H. Y.; Wang, R. Q.; Sheng, W. J.; Zhen, Y. S., The development of human serum albumin-based drugs and relevant fusion proteins for cancer therapy. Int J Biol Macromol 2021, 187, 24-34.
    Ehrlich, G. K.; Michel, H.; Truitt, T.; Riboulet, W.; Pop-Damkov, P.; Goelzer, P.; Hainzl, D.; Qureshi, F.; Lueckel, B.; Danho, W.; Conde-Knape, K.; Konkar, A., Preparation and characterization of albumin conjugates of a truncated peptide YY analogue for half-life extension. Bioconjug Chem 2013, 24 (12), 2015-2024.
    Merlot, A. M.; Kalinowski, D. S.; Richardson, D. R., Unraveling the mysteries of serum albumin-more than just a serum protein. Front Physiol 2014, 5, 299.
    Zhao, P.; Wang, Y.; Wu, A.; Rao, Y.; Huang, Y., Roles of Albumin-Binding Proteins in Cancer Progression and Biomimetic Targeted Drug Delivery. Chembiochem 2018, 19 (17), 1796-1805.
    Park, C. R.; Kim, H. Y.; Song, M. G.; Lee, Y. S.; Youn, H.; Chung, J. K.; Cheon, G. J.; Kang, K. W., Efficacy and Safety of Human Serum Albumin-Cisplatin Complex in U87MG Xenograft Mouse Models. Int J Mol Sci 2020, 21 (21) 7932.
    Zhang, Z.; Zhang, Y.; Song, S.; Yin, L.; Sun, D.; Gu, J., Recent advances in the bioanalytical methods of polyethylene glycols and PEGylated pharmaceuticals. J Sep Sci 2020, 43 (9-10), 1978-1997.
    Pasut, G.; Canal, F.; Dalla Via, L.; Arpicco, S.; Veronese, F. M.; Schiavon, O., Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid. J Control Release 2008, 127 (3), 239-248.
    Alconcel, S. N. S.; Baas, A. S.; Maynard, H. D., FDA-approved poly(ethylene glycol)–protein conjugate drugs. Polymer Chemistry 2011, 2 (7) 1442.
    Paula C.A. Rodrigues, U. B., Peter Schumacher, Thomas Roth, Heinz H. Fiebig, Clemens Unger, Luigi Messori, PierLuigi Orioli, Dietrich H. Paper, Rolf Mülhaupt, Felix Kratz, Acid-sensitive polyethylene glycol conjugates of doxorubicin: preparation, in vitro efficacy and intracellular distribution. Bioorganic & Medicinal Chemistry 1999, 7 (11), 2517-2524.
    Ivens, I. A.; Achanzar, W.; Baumann, A.; Brandli-Baiocco, A.; Cavagnaro, J.; Dempster, M.; Depelchin, B. O.; Rovira, A. R.; Dill-Morton, L.; Lane, J. H.; Reipert, B. M.; Salcedo, T.; Schweighardt, B.; Tsuruda, L. S.; Turecek, P. L.; Sims, J., PEGylated Biopharmaceuticals: Current Experience and Considerations for Nonclinical Development. Toxicol Pathol 2015, 43 (7), 959-983.
    Shah, Z.; Gohar, U. F.; Jamshed, I.; Mushtaq, A.; Mukhtar, H.; Zia-Ui-Haq, M.; Toma, S. I.; Manea, R.; Moga, M.; Popovici, B., Podophyllotoxin: History, Recent Advances and Future Prospects. Biomolecules 2021, 11 (4) 603.
    Cheng, W. H.; Shang, H.; Niu, C.; Zhang, Z. H.; Zhang, L. M.; Chen, H.; Zou, Z. M., Synthesis and Evaluation of New Podophyllotoxin Derivatives with in Vitro Anticancer Activity. Molecules 2015, 20 (7), 12266-12279.
    Liu, Y. Q.; Tian, J.; Qian, K.; Zhao, X. B.; Morris-Natschke, S. L.; Yang, L.; Nan, X.; Tian, X.; Lee, K. H., Recent progress on C-4-modified podophyllotoxin analogs as potent antitumor agents. Med Res Rev 2015, 35 (1), 1-62.
    Motyka, S.; Jafernik, K.; Ekiert, H.; Sharifi-Rad, J.; Calina, D.; Al-Omari, B.; Szopa, A.; Cho, W. C., Podophyllotoxin and its derivatives: Potential anticancer agents of natural origin in cancer chemotherapy. Biomed Pharmacother 2023, 158, 114145.
    Shen, S.; Tong, Y.; Luo, Y.; Huang, L.; Gao, W., Biosynthesis, total synthesis, and pharmacological activities of aryltetralin-type lignan podophyllotoxin and its derivatives. Nat Prod Rep 2022, 39 (9), 1856-1875.
    Zi, C. T.; Yang, L.; Kong, Q. H.; Li, H. M.; Yang, X. Z.; Ding, Z. T.; Jiang, Z. H.; Hu, J. M.; Zhou, J., Glucoside Derivatives Of Podophyllotoxin: Synthesis, Physicochemical Properties, And Cytotoxicity. Drug Des Devel Ther 2019, 13, 3683-3692.
    Pohlit, H.; Worm, M.; Langhanki, J.; Berger-Nicoletti, E.; Opatz, T.; Frey, H., Silver Oxide Mediated Monotosylation of Poly(ethylene glycol) (PEG): Heterobifunctional PEG via Polymer Desymmetrization. Macromolecules 2017, 50 (23), 9196-9206.
    Chen, Y.; Zhang, P.; Liu, S.; Pahovnik, D.; Zagar, E.; Zhao, J.; Zhang, G., Noncovalent Protection for Direct Synthesis of alpha-Amino-omega-hydroxyl Poly(ethylene oxide). ACS Macro Lett 2021, 10 (6), 737-743.
    Hong, C.; Alser, O.; Gebran, A.; He, Y.; Joo, W.; Kokoroskos, N.; Velmahos, G.; Olsen, B. D.; Hammond, P. T., Modulating Nanoparticle Size to Understand Factors Affecting Hemostatic Efficacy and Maximize Survival in a Lethal Inferior Vena Cava Injury Model. ACS Nano 2022, 16 (2), 2494-2510.
    Sk, U. H.; Dixit, D.; Sen, E., Comparative study of microtubule inhibitors--estramustine and natural podophyllotoxin conjugated PAMAM dendrimer on glioma cell proliferation. Eur J Med Chem 2013, 68, 47-57.
    Song, H. Y.; Ngai, M. H.; Song, Z. Y.; MacAry, P. A.; Hobley, J.; Lear, M. J., Practical synthesis of maleimides and coumarin-linked probes for protein and antibody labelling via reduction of native disulfides. Org Biomol Chem 2009, 7 (17), 3400-3406.
    Mehtala, J. G.; Kulczar, C.; Lavan, M.; Knipp, G.; Wei, A., Cys34-PEGylated Human Serum Albumin for Drug Binding and Delivery. Bioconjug Chem 2015, 26 (5), 941-949.

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