臺灣博碩士論文加值系統

本論文描述了對由萘二甲醯亞胺二肽構成的水凝膠其合成與特性進行系統化研究的方法。四種水凝膠因子（NI-FG、NI-FA,、NI-FV、以及NI-FI）被設計並合成，這些水凝膠因子的疏水性透過選用帶有不同的烷基的胺基酸（甘胺酸、丙胺酸、纈胺酸、異白胺酸）受到調控，因而具有凝膠與螢光特性上的差異。確認了萘二甲醯亞胺二肽在中性酸鹼值下形成水凝膠的條件。以穿透式電子顯微影像觀察其形成的奈米胜肽管柱結構。螢光光譜中可觀察到鹼性溶液中出現的內電荷轉移現象。另外，透過使用哌嗪在萘二甲醯亞胺發光團上進行的化學修飾，可達成顏色的調整並引入光誘導電子轉移機制強化可能的應用性。基於以上成果，萘二甲醯亞胺二肽材料展現出極佳的生醫電子領域的應用潛力，包括應用於生物顯影、藥物傳遞、酸鹼感測等等。此研究提供了一種應用於螢光水相自組裝小分子有效的分子設計策略。

A systematic study of the synthesis and characterization of self-assembly naphthalimide-dipeptide hydrogels is described in this thesis. Four hydrogelators, NI-FG, NI-FA, NI-FV, and NI-FI were designed and synthesized. The hydrophobicity of the hydrogelators was regulated by changing the peptide sequence with amino acids containing alkyl side chains, i.e., glycine, alanine, valine, and isoleucine, which led to the differences in the gelation and fluorescence properties. The condition of hydrogel transition under neutral pH environment is verified. Formation of self-assembled nanotubes was examined under the transmission electron microscope. The fluorescence spectra showed an internal charge transfer band in basic solutions. And a chemical modification on the naphthalimide fluorophore using piperazine was introduced to adjust the color and to allow photoinduced electron transfer to enhance possible applications. Based on the above results, naphthalimide-dipeptide materials open up remarkable potential in biomedical electronic applications, such as bioimaging, drug delivery, pH sensing, and etc. This research provides a promising strategy in molecular designing of the fluorescent aqueous self-assembling small molecules.

English Abstract i
Chinese Abstract ii
Acknowledgement iii
Table of Contents v
List of Tables vi
List of Figures vii
Notations xi
I. Introduction 1
1.1 Self-assembled Supramolecular Hydrogels 1
1.2 Environment-sensitive Fluorophores 7
1.3 1,8-Naphthalimide Fluorescence Sensors 11
II. Research Methods 13
2.1 List of Materials Used 13
2.2 List of Instruments Used 14
2.3 Experiment Methods 14
III. Experiment 18
3.1 Foreword 18
3.2 Experiment Design 19
3.3 Synthetic Schemes 20
IV. Results and Discussion 34
4.1 Gelation Condition 34
4.2 Self-assembled Nanostructures 40
4.3 Fluorescence Properties 48
4.4 Chemical Modified Naphthalimide Fluorophore 51
V. Conclusion 55
Bibliographies 57
Appendixes 63

[1]. Flory, P. J. (1974). Introductory lecture. Faraday Discuss Chem Soc 57.
[2]. Burchard, W. & Ross-Murphy, S. B. (1990). Physical Networks: Polymers and Gels. pp. 1-14. Elsevier Applied Science, London.
[3]. Demouveaux, B., Gouyer, V., Gottrand, F., Narita, T. & Desseyn, J. L. (2018). Gel-forming mucin interactome drives mucus viscoelasticity. Adv Colloid Interface Sci 252, 69-82.
[4]. Campbell, L., Raikos, V. & Euston, S. R. (2003). Modification of functional properties of egg-white proteins. Nahrung 47(6), 369-376.
[5]. Ewoldt, R. H., Winegard, T. M. & Fudge, D. S. (2011). Non-linear viscoelasticity of hagfish slime. Int J Nonlin Mech 46(4), 627-636.
[6]. Taylor, C. V. (1923). The contractile vacuole in Euplotes: An example of the sol-gel reversibility of cytoplasm. J Exp Zool 37(3), 259-289.
[7]. Roy, N., Saha, N., Kitano, T. & Saha, P. (2012). Biodegradation of PVP-CMC hydrogel film: a useful food packaging material. Carbohydr Polym 89(2), 346-353.
[8]. Rudzinski, W. E., Dave, A. M., Vaishanav, U. H., Kumbar, S. G., Kulkarni, A. R. & Aminabhavi, T. M. (2002). Hydrogels as controlled release devices in agriculture. Des Monomers Polym 5(1), 39-65.
[9]. Chen, Y., Chen, L., Bai, H. & Li, L. (2013). Graphene oxide–chitosan composite hydrogels as broad-spectrum adsorbents for water purification. J Mater Chem A 1(6), 1992-2001.
[10]. Qiu, Y. & Park, K. (2012). Environment-sensitive hydrogels for drug delivery. Adv Drug Del Rev 64, 49-60.
[11]. Kashyap, N., Kumar, N. & Kumar, M. N. (2005). Hydrogels for pharmaceutical and biomedical applications. Crit Rev Ther Drug Carrier Syst 22(2), 107-149.
[12]. Cartmell, J. V. & Sturtevant, W. R. (1992). Transparent hydrogel wound dressing. US5106629A.
[13]. Drury, J. L. & Mooney, D. J. (2003). Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials 24(24), 4337-4351.
[14]. Holtz, J. H. & Asher, S. A. (1997). Polymerized colloidal crystal hydrogel films as intelligent chemical sensing materials. Nature 389(6653), 829-832.
[15]. Lee, Y. J. & Braun, P. V. (2003). Tunable Inverse Opal Hydrogel pH Sensors. Adv Mater 15(78), 563-566.
[16]. Lei, M. (2010). Hydrogel-actuated micromirrors for optical sensing. US7688450B2.
[17]. Russell, R. J., Pishko, M. V., Gefrides, C. C., Mcshane, M. J. & Coté, G. L. (1999). A Fluorescence-Based Glucose Biosensor Using Concanavalin A and Dextran Encapsulated in a Poly(ethylene glycol) Hydrogel. Anal Chem 71(15), 3126-3132.
[18]. Davis, J. T. & Spada, G. P. (2007). Supramolecular architectures generated by self-assembly of guanosine derivatives. Chem Soc Rev 36(2), 296-313.
[19]. Hsu, S. M., Lin, Y. C., Chang, J. W., Liu, Y. H. & Lin, H. C. (2014). Intramolecular interactions of a phenyl/perfluorophenyl pair in the formation of supramolecular nanofibers and hydrogels. Angew Chem Int Ed Engl 53(7), 1921-1927.
[20]. Madhusudan Makwana, K. & Mahalakshmi, R. (2015). Implications of aromatic-aromatic interactions: From protein structures to peptide models. Protein Sci 24(12), 1920-1933.
[21]. Ozbas, B., Kretsinger, J., Rajagopal, K., Schneider, J. P. & Pochan, D. J. (2004). Salt-Triggered Peptide Folding and Consequent Self-Assembly into Hydrogels with Tunable Modulus. Macromolecules 37(19), 7331-7337.
[22]. Terech, P. & Weiss, R. G. (1997). Low Molecular Mass Gelators of Organic Liquids and the Properties of Their Gels. Chem Rev 97(8), 3133-3160.
[23]. Draper, E. R. & Adams, D. J. (2017). Low-Molecular-Weight Gels: The State of the Art. Chem 3(3), 390-410.
[24]. Kunitake, T., Okahata, Y., Shimomura, M., Yasunami, S. I. & Takarabe, K. (1981). Formation of Stable Bilayer Assemblies in Water from Single-Chain Amphiphiles - Relationship between the Amphiphile Structure and the Aggregate Morphology. J Am Chem Soc 103(18), 5401-5413.
[25]. Estroff, L. A. & Hamilton, A. D. (2004). Water gelation by small organic molecules. Chem Rev 104(3), 1201-1218.
[26]. Aggeli, A., Nyrkova, I. A., Bell, M., Harding, R., Carrick, L., Mcleish, T. C., Semenov, A. N. & Boden, N. (2001). Hierarchical self-assembly of chiral rod-like molecules as a model for peptide beta -sheet tapes, ribbons, fibrils, and fibers. Proc Natl Acad Sci U S A 98(21), 11857-11862.
[27]. Ziserman, L., Lee, H. Y., Raghavan, S. R., Mor, A. & Danino, D. (2011). Unraveling the mechanism of nanotube formation by chiral self-assembly of amphiphiles. J Am Chem Soc 133(8), 2511-2517.
[28]. Gao, X. & Matsui, H. (2005). Peptide-Based Nanotubes and Their Applications in Bionanotechnology. Adv Mater 17(17), 2037-2050.
[29]. Matsui, H., Porrata, P. & Douberly, G. E. (2001). Protein Tubule Immobilization on Self-Assembled Monolayers on Au Substrates. Nano Lett 1(9), 461-464.
[30]. Reches, M. & Gazit, E. (2003). Casting metal nanowires within discrete self-assembled peptide nanotubes. Science 300(5619), 625-627.
[31]. Ryu, J., Kim, S. W., Kang, K. & Park, C. B. (2010). Mineralization of self-assembled peptide nanofibers for rechargeable lithium ion batteries. Adv Mater 22(48), 5537-5541.
[32]. Suri, S. S., Fenniri, H. & Singh, B. (2007). Nanotechnology-based drug delivery systems. J Occup Med Toxicol 2, 16.
[33]. Wang, Q., Zhang, X., Zheng, J. & Liu, D. (2014). Self-assembled peptide nanotubes as potential nanocarriers for drug delivery. RSC Advances 4(48).
[34]. Park, J. H., Kwon, S., Nam, J. O., Park, R. W., Chung, H., Seo, S. B., Kim, I. S., Kwon, I. C. & Jeong, S. Y. (2004). Self-assembled nanoparticles based on glycol chitosan bearing 5beta-cholanic acid for RGD peptide delivery. J Control Release 95(3), 579-588.
[35]. Silva, G. A., Czeisler, C., Niece, K. L., Beniash, E., Harrington, D. A., Kessler, J. A. & Stupp, S. I. (2004). Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science 303(5662), 1352-1355.
[36]. Goodwin, P. M., Ambrose, W. P. & Keller, R. A. (1996). Single-molecule detection in liquids by laser-induced fluorescence. Acc Chem Res 29(12), 607-613.
[37]. Uno, S. N., Kamiya, M., Yoshihara, T., Sugawara, K., Okabe, K., Tarhan, M. C., Fujita, H., Funatsu, T., Okada, Y., Tobita, S. & Urano, Y. (2014). A spontaneously blinking fluorophore based on intramolecular spirocyclization for live-cell super-resolution imaging. Nat Chem 6(8), 681-689.
[38]. Juette, M. F. & Bewersdorf, J. (2010). Three-dimensional tracking of single fluorescent particles with submillisecond temporal resolution. Nano Lett 10(11), 4657-4663.
[39]. Vetrone, F., Naccache, R., Zamarron, A., Juarranz De La Fuente, A., Sanz-Rodriguez, F., Martinez Maestro, L., Martin Rodriguez, E., Jaque, D., Garcia Sole, J. & Capobianco, J. A. (2010). Temperature sensing using fluorescent nanothermometers. ACS Nano 4(6), 3254-3258.
[40]. Basabe-Desmonts, L., Reinhoudt, D. N. & Crego-Calama, M. (2007). Design of fluorescent materials for chemical sensing. Chem Soc Rev 36(6), 993-1017.
[41]. Korostynska, O., Arshak, K., Gill, E. & Arshak, A. (2007). State Key Laboratory of Nonlinear Mechanics (LNM), Institute of Mechanics, Chinese Academy of Sciences, Beijing 100080, China. Sensors (Basel) 7(12), 3027-3042.
[42]. Gunnlaugsson, T., Glynn, M., Tocci, G. M., Kruger, P. E. & Pfeffer, F. M. (2006). Anion recognition and sensing in organic and aqueous media using luminescent and colorimetric sensors. Coord Chem Rev 250(23-24), 3094-3117.
[43]. Caricato, M., Coluccini, C., Vander Griend, D. A., Forni, A. & Pasini, D. (2013). From red to blue shift: switching the binding affinity from the acceptor to the donor end by increasing the π-bridge in push–pull chromophores with coordinative ends. New J Chem 37(9).
[44]. Pasini, D., Righetti, P. P. & Rossi, V. (2002). Malonate Crown Ethers as Building Blocks for Novel D-π-A Chromophores. Org Lett 4(1), 23-26.
[45]. De Silva, A. P., Gunaratne, H. Q. N., Gunnlaugsson, T., Huxley, A. J. M., Mccoy, C. P., Rademacher, J. T. & Rice, T. E. (1997). Signaling Recognition Events with Fluorescent Sensors and Switches. Chem Rev 97(5), 1515-1566.
[46]. Callan, J. F., De Silva, A. P. & Magri, D. C. (2005). Luminescent sensors and switches in the early 21st century. Tetrahedron 61(36), 8551-8588.
[47]. Bojinov, V. B., Georgiev, N. I. & Bosch, P. (2009). Design and synthesis of highly photostable yellow-green emitting 1,8-naphthalimides as fluorescent sensors for metal cations and protons. J Fluoresc 19(1), 127-139.
[48]. Gao, M. & Tang, B. Z. (2017). Fluorescent Sensors Based on Aggregation-Induced Emission: Recent Advances and Perspectives. ACS Sens 2(10), 1382-1399.
[49]. Hong, Y., Lam, J. W. & Tang, B. Z. (2009). Aggregation-induced emission: phenomenon, mechanism and applications. Chem Commun (Camb) (29), 4332-4353.
[50]. Hong, Y., Lam, J. W. & Tang, B. Z. (2011). Aggregation-induced emission. Chem Soc Rev 40(11), 5361-5388.
[51]. John, H. P. (1990). The UV-Visible Absorption and Fluorescence of some Substituted 1,8- Naphthalimides and Naphthlic Anhydrides. J Chem Soc Perk Trans 2 5, 837-842.
[52]. Gan, J.-A., Song, Q. L., Hou, X. Y., Chen, K. & Tian, H. (2004). 1,8-Naphthalimides for non-doping OLEDs: the tunable emission color from blue, green to red. J Photochem Photobiol A: Chem 162(2-3), 399-406.
[53]. Banerjee, S., Veale, E. B., Phelan, C. M., Murphy, S. A., Tocci, G. M., Gillespie, L. J., Frimannsson, D. O., Kelly, J. M. & Gunnlaugsson, T. (2013). Recent advances in the development of 1,8-naphthalimide based DNA targeting binders, anticancer and fluorescent cellular imaging agents. Chem Soc Rev 42(4), 1601-1618.
[54]. Grabtschev, I. K., Moneva, I. T., Wolarz, E. & Bauman, D. (1996). New unsaturated 1,8-naphthalimide dyes for use in nematic liquid crystals. Z Naturforsch, A: Phys Sci 51(12), 1185-1191.
[55]. Veale, E. B., Frimannsson, D. O., Lawler, M. & Gunnlaugsson, T. (2009). 4-Amino-1,8-naphthalimide-based Troger's bases as high affinity DNA targeting fluorescent supramolecular scaffolds. Org Lett 11(18), 4040-4043.
[56]. Hsu, S.-M., Chakravarthy, R. D., Cheng, H., Wu, F.-Y., Lai, T.-S. & Lin, H.-C. (2018). The role of aromatic side chains on the supramolecular hydrogelation of naphthalimide/dipeptide conjugates. New J Chem 42(6), 4443-4449.
[57]. Yeh, M. Y., Huang, C. T., Lai, T. S., Chen, F. Y., Chu, N. T., Tseng, D. T., Hung, S. C. & Lin, H. C. (2016). Effect of Peptide Sequences on Supramolecular Interactions of Naphthaleneimide/Tripeptide Conjugates. Langmuir 32(30), 7630-7638.
[58]. Huang, Y.-T. (2016). Napthalimide-based Self-assembled Nanostructures and Their Luminescence Characteristics. In Materials Science and Engineering: National Chiao Tung University.
[59]. Hsu, S.-M. (2014). Design, Synthesis and Physical Properties of Supramolecular Hydrogels: The Versatility of Ultrashort Peptides. In Materials Science and Engineering, pp. 107. National Chiao Tung University.
[60]. Gan, J., Chen, K. C., Chang, C. P. & Tian, H. (2003). Luminescent properties and photo-induced electron transfer of naphthalimides with piperazine substituent. Dyes Pigments 57(1), 21-28.
[61]. Li, H.-T., Jiang, Z.-Q., Zheng, J., Wang, X., Pan, Y., Wang, F. & Yu, S.-Q. (2006). A novel 1,8-naphthalimide probe: synthesis and interactions with nucleic acid and its precursor. Res Chem Intermed 32(1), 43-57.
[62]. Wang, L. L., Meiyan; Chen, Zhijun; Huang, Zhuo; Tian, He; Chen, Lirong. (2013). 萘酰亚胺衍生物及其用途. CN103012372A.
[63]. Chandrika, N. T., Shrestha, S. K., Ngo, H. X. & Garneau-Tsodikova, S. (2016). Synthesis and investigation of novel benzimidazole derivatives as antifungal agents. Biorg Med Chem 24(16), 3680-3686.
[64]. Wurth, C., Grabolle, M., Pauli, J., Spieles, M. & Resch-Genger, U. (2013). Relative and absolute determination of fluorescence quantum yields of transparent samples. Nat Protoc 8(8), 1535-1550.