本論文第一部分為藉由改變在寡聚胺基酸上的微少官能基, 改變分子的奈米排列及流變特性, 進而得到劇烈的溫感性水膠. 另一個工作為呈現一個新型的感溫型且具生物相容性的水膠材料, 並將其攜帶抗體藥物來達到藥物緩釋的效果. 從累積性的藥物釋放數據, 可以知道在一個月內, 藥物從水膠內可釋放出90%. 而且這個水膠材料在體外試驗中無明顯毒性. 此論文不但說明如何藉由改變官能基來改變胜肽的二級結構, 進而改變分子的奈米排列以及流變特性(第三章); 而且也確認了一個新型的生物良好性水膠材料,它有用在包覆抗體並達到緩釋目的的潛力(第四章).
總言, 這寡聚型胜肽胺基酸水膠, 在這篇論文被描述出, 並提出可應用在藥物傳輸.

The first part of this thesis focuses on a slight change in the functional group of the oligopeptide block incorporated into the Poloxamer triblock copolymer that led to drastically different hierarchical assembly behavior and rheological properties in aqueous media for the application as thermo-sensitive hydrogel. Another work presents a new thermosensitive biocompatible oligopeptide-containing hydrogel which is novel for carrying antibody drug - bevacizumab with extended release. The accumulative extended release of bevacizumab in vitro from hydrogel was approximately 90% over a period of one month. Moreover, the in vitro cytotoxicity of oligopeptide-containing Poloxamer copolymer aqueous solution was found to be low on the human retinal pigment epithelial cells.
These results not only resolve how the change of the peptide functional group would modify the secondary structure supramolecular assembly behavior and rheological properties of the block copolymer (chapter 3), but also identify a new biocompatible thermo-sensitive hydrogel with low critical gelation concentration (CGC), which may be used in typical diffusion-controlled drug release (chapter 4).
In summary, the oligopeptide thermosensitive hydrogel can be used in the field of drug delivery is described in this thesis.

[1] Hoare TR, Kohane DS. Hydrogels in drug delivery: Progress and challenges. Polymer. 2008;49:1993-2007.
[2] Misra GP, Singh RSJ, Aleman TS, Jacobson SG, Gardner TW, Lowe TL. Subconjunctivally implantable hydrogels with degradable and thermoresponsive properties for sustained release of insulin to the retina. Biomaterials. 2009;30:6541-7.
[3] Al-Abd AM, Hong K-Y, Song S-C, Kuh H-J. Pharmacokinetics of doxorubicin after intratumoral injection using a thermosensitive hydrogel in tumor-bearing mice. Journal of Controlled Release. 2010;142:101-7.
[4] Sivakumaran D, Maitland D, Hoare T. Injectable microgel-hydrogel composites for prolonged small-molecule drug delivery. Biomacromolecules. 2011;12:4112-20.
[5] Turturro SB, Guthrie MJ, Appel AA, Drapala PW, Brey EM, Pérez-Luna VH, et al. The effects of cross-linked thermo-responsive PNIPAAm-based hydrogel injection on retinal function. Biomaterials. 2011;32:3620-6.
[6] Wang CH, Hwang YS, Chiang PR, Shen CR, Hong WH, Hsiue GH. Extended release of bevacizumab by thermosensitive biodegradable and biocompatible hydrogel. Biomacromolecules. 2011;13:40-8.
[7] Dankers PYW, Hermans TM, Baughman TW, Kamikawa Y, Kieltyka RE, Bastings M, et al. Hierarchical Formation of Supramolecular Transient Networks in Water: A Modular Injectable Delivery System. Advanced Materials. 2012.
[8] Kang X, Cheng Z, Yang D, Ma Pa, Shang M, Peng C, et al. Design and Synthesis of Multifunctional Drug Carriers Based on Luminescent Rattle‐Type Mesoporous Silica Microspheres with a Thermosensitive Hydrogel as a Controlled Switch. Advanced Functional Materials. 2012;22:1470-81.
[9] Qiu Y, Park K. Environment-sensitive hydrogels for drug delivery. Advanced drug delivery reviews. 2012.
[10] Rösler A, Vandermeulen GW, Klok H-A. Advanced drug delivery devices via self-assembly of amphiphilic block copolymers. Advanced Drug Delivery Reviews. 2012.
[11] Chung HJ, Park TG. Self-assembled and nanostructured hydrogels for drug delivery and tissue engineering. Nano Today. 2009;4:429-37.
[12] Tan H, Ramirez CM, Miljkovic N, Li H, Rubin JP, Marra KG. Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering. Biomaterials. 2009;30:6844-53.
[13] Balakrishnan B, Banerjee R. Biopolymer-based hydrogels for cartilage tissue engineering. Chemical Reviews. 2011;111:4453-74.
[14] Censi R, Schuurman W, Malda J, Di Dato G, Burgisser PE, Dhert WJ, et al. A Printable Photopolymerizable Thermosensitive p (HPMAm‐lactate)‐PEG Hydrogel for Tissue Engineering. Advanced Functional Materials. 2011;21:1833-42.
[15] Kim B-S, Park I-K, Hoshiba T, Jiang H-L, Choi Y-J, Akaike T, et al. Design of artificial extracellular matrices for tissue engineering. Progress in Polymer Science. 2011;36:238-68.
[16] Van Vlierberghe S, Dubruel P, Schacht E. Biopolymer-based hydrogels as scaffolds for tissue engineering applications: a review. Biomacromolecules. 2011;12:1387-408.
[17] Ekenseair AK, Boere KW, Tzouanas SN, Vo TN, Kasper FK, Mikos AG. Structure–Property Evaluation of Thermally and Chemically Gelling Injectable Hydrogels for Tissue Engineering. Biomacromolecules. 2012;13:2821-30.
[18] Tan R, She Z, Wang M, Fang Z, Liu Y, Feng Q. Thermo-sensitive alginate-based injectable hydrogel for tissue engineering. Carbohydrate Polymers. 2012;87:1515-21.
[19] Moon HJ, Park MH, Joo MK, Jeong B. Temperature-responsive compounds as in situ gelling biomedical materials. Chemical Society Reviews. 2012;41:4860-83.
[20] Oh HJ, Joo MK, Sohn YS, Jeong B. Secondary Structure Effect of Polypeptide on Reverse Thermal Gelation and Degradation of l/dl-Poly (alanine)–Poloxamer–l/dl-Poly (alanine) Copolymers. Macromolecules. 2008;41:8204-9.
[21] Kim EH, Joo MK, Bahk KH, Park MH, Chi B, Lee YM, et al. Reverse thermal gelation of PAF-PLX-PAF block copolymer aqueous solution. Biomacromolecules. 2009;10:2476-81.
[22] Jeong Y, Joo MK, Bahk KH, Choi YY, Kim HT, Kim WK, et al. Enzymatically degradable temperature-sensitive polypeptide as a new in-situ gelling biomaterial. Journal of Controlled Release. 2009;137:25-30.
[23] Choi BG, Park MH, Cho SH, Joo MK, Oh HJ, Kim EH, et al. Thermal gelling polyalanine-poloxamine-polyalanine aqueous solution for chondrocytes 3D culture: Initial concentration effect. Soft Matter. 2010;7:456-62.
[24] Moon HJ, Choi BG, Park MH, Joo MK, Jeong B. Enzymatically degradable thermogelling poly (alanine-co-leucine)-poloxamer-poly (alanine-co-leucine). Biomacromolecules. 2011;12:1234-42.
[25] Shinde UP, Joo MK, Moon HJ, Jeong B. Sol–gel transition of PEG–PAF aqueous solution and its application for hGH sustained release. Journal of Materials Chemistry. 2012;22:6072-9.
[26] Li F, Li S, El Ghzaoui A, Nouailhas H, Zhuo R. Synthesis and gelation properties of PEG-PLA-PEG triblock copolymers obtained by coupling monohydroxylated PEG-PLA with adipoyl chloride. Langmuir. 2007;23:2778-83.
[27] Jeong B, Bae YH, Lee DS, Kim SW. Biodegradable block copolymers as injectable drug-delivery systems. Nature. 1997;388:860-2.
[28] Jeong B, Bae YH, Kim SW. Thermoreversible gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions. Macromolecules. 1999;32:7064-9.
[29] Choi BG, Park MH, Cho SH, Joo MK, Oh HJ, Kim EH, et al. < i> In situ</i> thermal gelling polypeptide for chondrocytes 3D culture. Biomaterials. 2010;31:9266-72.
[30] Altunbas A, Pochan DJ. Peptide-based and polypeptide-based hydrogels for drug delivery and tissue engineering. Peptide-Based Materials: Springer; 2012. p. 135-67.
[31] Liang G, Yang Z, Zhang R, Li L, Fan Y, Kuang Y, et al. Supramolecular Hydrogel of a d-Amino Acid Dipeptide for Controlled Drug Release in Vivo†. Langmuir. 2009;25:8419-22.
[32] Zhang H, Yu L, Ding J. Roles of hydrophilic homopolymers on the hydrophobic-association-induced physical gelling of amphiphilic block copolymers in water. Macromolecules. 2008;41:6493-9.
[33] Bae SJ, Joo MK, Jeong Y, Kim SW, Lee W-K, Sohn YS, et al. Gelation behavior of poly (ethylene glycol) and polycaprolactone triblock and multiblock copolymer aqueous solutions. Macromolecules. 2006;39:4873-9.
[34] Ivanova R, Lindman B, Alexandridis P. Evolution in structural polymorphism of pluronic F127 poly (ethylene oxide)-poly (propylene oxide) block copolymer in ternary systems with water and pharmaceutically acceptable organic solvents: from “glycols” to “oils”. Langmuir. 2000;16:9058-69.
[35] Masayuki Y, Mizue M, Noriko Y, Teruo O, Yasuhisa S, Kazunori K, et al. Polymer micelles as novel drug carrier: adriamycin-conjugated poly (ethylene glycol)-poly (aspartic acid) block copolymer. Journal of controlled release. 1990;11:269-78.
[36] Yokoyama M, Miyauchi M, Yamada N, Okano T, Sakurai Y, Kataoka K, et al. Characterization and anticancer activity of the micelle-forming polymeric anticancer drug adriamycin-conjugated poly (ethylene glycol)-poly (aspartic acid) block copolymer. Cancer research. 1990;50:1693-700.
[37] Harada A, Kataoka K. Novel polyion complex micelles entrapping enzyme molecules in the core: preparation of narrowly-distributed micelles from lysozyme and poly (ethylene glycol)-poly (aspartic acid) block copolymer in aqueous medium. Macromolecules. 1998;31:288-94.
[38] Kakizawa Y, Miyata K, Furukawa S, Kataoka K. Size‐Controlled Formation of a Calcium Phosphate‐Based Organic–Inorganic Hybrid Vector for Gene Delivery Using Poly (ethylene glycol)‐block‐poly (aspartic acid). Advanced Materials. 2004;16:699-702.
[39] Liu C, Chen Y, Chen J. Synthesis and characteristics of pH-sensitive semi-interpenetrating polymer network hydrogels based on konjac glucomannan and poly (aspartic acid) for in vitro drug delivery. Carbohydrate Polymers. 2010;79:500-6.
[40] Zohuriaan‐Mehr M, Pourjavadi A, Salimi H, Kurdtabar M. Protein‐and homo poly (amino acid)‐based hydrogels with super‐swelling properties. Polymers for Advanced Technologies. 2009;20:655-71.
[41] Shu S, Zhang X, Teng D, Wang Z, Li C. Polyelectrolyte nanoparticles based on water-soluble chitosan–poly (l-aspartic acid)–polyethylene glycol for controlled protein release. Carbohydrate research. 2009;344:1197-204.
[42] Zhao Y, Kang J, Tan T. Salt-, pH-and temperature-responsive semi-interpenetrating polymer network hydrogel based on poly (aspartic acid) and poly (acrylic acid). Polymer. 2006;47:7702-10.
[43] Choi YY, Joo MK, Sohn YS, Jeong B. Significance of secondary structure in nanostructure formation and thermosensitivity of polypeptide block copolymers. Soft Matter. 2008;4:2383-7.
[44] Hong D-W, Lai P-L, Ku K-L, Lai Z-T, Chu I. Biodegradable in situ gel-forming controlled vancomycin delivery system based on a thermosensitive mPEG-PLCPPA hydrogel. Polymer Degradation and Stability. 2013.
[45] Huang J, Hastings CL, Duffy GP, Kelly HM, Raeburn J, Adams DJ, et al. Supramolecular hydrogels with reverse thermal gelation properties from (oligo) tyrosine containing block copolymers. Biomacromolecules. 2012;14:200-6.
[46] Liu M, Su H, Tan T. Synthesis and properties of thermo-and pH-sensitive poly (N-isopropylacrylamide)/polyaspartic acid IPN hydrogels. Carbohydrate Polymers. 2012;87:2425-31.
[47] Choi BG, Cho S-H, Lee H, Cha MH, Park K, Jeong B, et al. Thermoreversible Radial Growth of Micellar Assembly for Hydrogel Formation Using Zwitterionic Oligopeptide Copolymer. Macromolecules. 2011;44:2269-75.
[48] Kim JY, Park MH, Joo MK, Lee SY, Jeong B. End Groups Adjusting the Molecular Nano-Assembly Pattern and Thermal Gelation of Polypeptide Block Copolymer Aqueous Solution. Macromolecules. 2009;42:3147-51.
[49] Cheng Y, He C, Xiao C, Ding J, Zhuang X, Huang Y, et al. Decisive role of hydrophobic side groups of polypeptides in thermosensitive gelation. Biomacromolecules. 2012;13:2053-9.
[50] Park SH, Choi BG, Moon HJ, Cho S-H, Jeong B. Block sequence affects thermosensitivity and nano-assembly: PEG-l-PA-dl-PA and PEG-dl-PA-l-PA block copolymers. Soft Matter. 2011;7:6515-21.
[51] Choi YY, Jang JH, Park MH, Choi BG, Chi B, Jeong B. Block length affects secondary structure, nanoassembly and thermosensitivity of poly (ethylene glycol)-poly (L-alanine) block copolymers. Journal of Materials Chemistry. 2010;20:3416-21.
[52] Scott RA, Scheraga HA. Conformational Analysis of Macromolecules. III. Helical Structures of Polyglycine and Poly‐L‐Alanine. The Journal of Chemical Physics. 1966;45:2091.
[53] Inomata K, Iguchi Y, Mizutani K, Sugimoto H, Nakanishi E. Anisotropic Swelling Behavior Induced by Helix–Coil Transition in Liquid Crystalline Polypeptide Gels. ACS Macro Letters. 2012;1:807-10.
[54] Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. New England Journal of Medicine. 2006;355:1432-44.
[55] ATZENI F, TURIEL M, CAPSONI F, DORIA A, MERONI P, SARZI‐PUTTINI P. Autoimmunity and anti‐TNF‐α agents. Annals of the New York Academy of Sciences. 2005;1051:559-69.
[56] Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, Vollenhoven Rv, et al. The PREMIER study: a multicenter, randomized, double‐blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis & Rheumatism. 2006;54:26-37.
[57] Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. New England Journal of Medicine. 1997;337:1029-36.
[58] McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. Journal of clinical oncology. 1998;16:2825-33.
[59] Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, et al. Differential effects of gefitinib and cetuximab on non–small-cell lung cancers bearing epidermal growth factor receptor mutations. Journal of the National Cancer Institute. 2005;97:1185-94.
[60] Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. Journal of Clinical Oncology. 1996;14:737-44.
[61] Joy MS, Gipson DS, Powell L, MacHardy J, Jennette JC, Vento S, et al. Phase 1 trial of adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) study group. American Journal of Kidney Diseases. 2010;55:50-60.
[62] Tran L, Baars JW, Aarden L, Beijnen JH, Huitema AD. Pharmacokinetics of rituximab in patients with CD20 positive B-cell malignancies. Human antibodies. 2010;19:7-13.
[63] Tan AR, Moore DF, Hidalgo M, Doroshow JH, Poplin EA, Goodin S, et al. Pharmacokinetics of cetuximab after administration of escalating single dosing and weekly fixed dosing in patients with solid tumors. Clinical cancer research. 2006;12:6517-22.
[64] Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW, et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proceedings of the National Academy of Sciences. 2006;103:6315-20.
[65] Kong HJ, Kim ES, Huang Y-C, Mooney DJ. Design of biodegradable hydrogel for the local and sustained delivery of angiogenic plasmid DNA. Pharmaceutical research. 2008;25:1230-8.
[66] Ta HT, Dass CR, Larson I, Choong PF, Dunstan DE. A chitosan hydrogel delivery system for osteosarcoma gene therapy with pigment epithelium-derived factor combined with chemotherapy. Biomaterials. 2009;30:4815-23.
[67] Song B, Song J, Zhang S, Anderson MA, Ao Y, Yang C-Y, et al. Sustained local delivery of bioactive nerve growth factor in the central nervous system via tunable diblock copolypeptide hydrogel depots. Biomaterials. 2012.
[68] Ferrara N, Hillan KJ, Gerber H-P, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature reviews Drug discovery. 2004;3:391-400.
[69] Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England journal of medicine. 2004;350:2335-42.
[70] Willett CG, Boucher Y, di Tomaso E, Duda DG, Munn LL, Tong RT, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature medicine. 2004;10:145-7.
[71] Wang C-H, Wang W-T, Hsiue G-H. Development of polyion complex micelles for encapsulating and delivering amphotericin B. Biomaterials. 2009;30:3352-8.
[72] Hadjichristidis N, Iatrou H, Pitsikalis M, Sakellariou G. Synthesis of well-defined polypeptide-based materials via the ring-opening polymerization of α-amino acid N-carboxyanhydrides. Chemical reviews. 2009;109:5528-78.
[73] Koo AN, Lee HJ, Kim SE, Chang JH, Park C, Kim C, et al. Disulfide-cross-linked PEG-poly (amino acid) s copolymer micelles for glutathione-mediated intracellular drug delivery. Chemical Communications. 2008:6570-2.
[74] Huang T-W, Liu S-Y, Chuang Y-J, Hsieh H-Y, Tsai C-Y, Huang Y-T, et al. Self-aligned wet-cell for hydrated microbiology observation in TEM. Lab on a chip. 2012;12:340-7.
[75] Naik RR, Kirkpatrick SM, Stone MO. The thermostability of an α-helical coiled-coil protein and its potential use in sensor applications. Biosensors and Bioelectronics. 2001;16:1051-7.
[76] Painter PC, Tang WL, Graf JF, Thomson B, Coleman MM. Formation of molecular composites through hydrogen-bonding interactions. Macromolecules. 1991;24:3929-36.
[77] Kuo S-W, Chen C-J. Functional Polystyrene Derivatives Influence the Miscibility and Helical Peptide Secondary Structures of Poly (γ-benzyl l-glutamate). Macromolecules. 2012;45:2442-52.
[78] Zhang J-T, Petersen S, Thunga M, Leipold E, Weidisch R, Liu X, et al. Micro-structured smart hydrogels with enhanced protein loading and release efficiency. Acta Biomaterialia. 2010;6:1297-306.
[79] Lin Y, Qiao Y, Yan Y, Huang J. Thermo-responsive viscoelastic wormlike micelle to elastic hydrogel transition in dual-component systems. Soft Matter. 2009;5:3047-53.
[80] Serra L, Doménech J, Peppas NA. Drug transport mechanisms and release kinetics from molecularly designed poly (acrylic acid-< i> g</i>-ethylene glycol) hydrogels. Biomaterials. 2006;27:5440-51.
[81] Huang Y, Yu H, Xiao C. pH-sensitive cationic guar gum/poly (acrylic acid) polyelectrolyte hydrogels: Swelling and in vitro drug release. Carbohydrate polymers. 2007;69:774-83.
[82] Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, et al. Stem cell–like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer research. 2006;66:7843-8.
[83] Höbel S, Koburger I, John M, Czubayko F, Hadwiger P, Vornlocher HP, et al. Polyethylenimine/small interfering RNA‐mediated knockdown of vascular endothelial growth factor in vivo exerts anti‐tumor effects synergistically with Bevacizumab. The journal of gene medicine. 2010;12:287-300.